JP2006512359A - Dosage form containing CETP inhibitor and HMG-CoA reductase inhibitor - Google Patents

Abstract

The dosage form contains (1) an amorphous solid dispersion comprising a cholesteryl ester transfer protein inhibitor and an acidic concentrated polymer, and (2) an HMG-CoA reductase inhibitor. The amorphous solid dispersion and the HMG-CoA reductase inhibitor are combined together in the dosage form such that the amorphous solid dispersion and the HMG-CoA reductase inhibitor are substantially separated from each other in the dosage form. To be.

Description

Cross-reference to related applications Will be charged.

The present invention comprises (1) an amorphous solid dispersion comprising a cholesteryl ester transfer protein (CETP) inhibitor and an acidic concentrated polymer; and (2) an acid-sensitive HMG-CoA reductase inhibitor; Regarding dosage form.

  Inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMG-CoA reductase), an important enzyme that catalyzes the intracellular synthesis of cholesterol, are particularly important for low-density lipoprotein cholesterol. It is well known to result in reduced levels of. Therefore, it is believed that HMG-CoA reductase enzyme inhibitors may be useful as cholesterol lowering agents or fat lowering agents.

  CETP inhibitors are another class of compounds that can alter blood cholesterol levels, such as by increasing high density lipoprotein (HDL) cholesterol and lowering LDL cholesterol. CETP inhibitors have very low solubility in water. CETP inhibitors must therefore be formulated so as to be able to provide good bioavailability. One way to increase the bioavailability of CETP inhibitors is the formation of an amorphous solid dispersion of drug and concentrated polymer. See for example WO 02/11710 A2. For many CETP inhibitors, acidic thickening polymers provide the highest level of thickening.

  It is well known that elevated LDL cholesterol levels and low HDL cholesterol levels can be treated using a combination therapy of CETP inhibitors and HMG-CoA reductase inhibitors. For example, WO 02/13797 A2 relates to a pharmaceutical combination of a cholesteryl ester transfer protein inhibitor and atorvastatin. This application discloses that these compounds can generally be administered individually or together with a pharmaceutically acceptable carrier, solvent or diluent. These compounds may be administered individually or together in any conventional oral, parenteral or transdermal dosage form. For oral administration, the composition can take the form of solutions, suspensions, tablets, pills, capsules, powders, and the like.

  DeNinno et al., US Pat. No. 6,310,075 B1, relates to CETP inhibitors, pharmaceutical compositions containing such inhibitors and the use of such inhibitors. DeNinno et al. Discloses a pharmaceutical combination composition containing a CETP inhibitor and an HMG-CoA reductase inhibitor. DeNinno discloses that the compounds of the invention can be administered in the form of a pharmaceutical composition containing at least one of these compounds together with a pharmaceutically acceptable solvent, diluent or carrier. For oral administration, the pharmaceutical composition can take the form of solutions, suspensions, tablets, pills, capsules, powders, and the like. Similarly, DeNinno et al., US Pat. No. 6,197,786 B1, discloses a pharmaceutical combination containing a CETP inhibitor and an HMG-CoA reductase inhibitor.

  WO 00/38722 discloses a combination of CETP inhibitors and HMG-CoA reductase inhibitors for cardiovascular indications. This pharmaceutical composition includes those suitable for oral, rectal, topical, buccal and parenteral administration. This application discloses solid dosage forms for oral administration, including capsules, tablets, pills, powders, gel caps and granules.

  Schmeck et al. US Pat. No. 5,932,587 discloses another class of CETP inhibitors. Schmeck et al. Disclose that CETP inhibitors can be used in combination with certain HMG-CoA reductase inhibitors, such as statins including atorvastatin.

  However, despite the desire to combine CETP inhibitors and HMG-CoA reductase inhibitors into single dosage forms, combining CETP inhibitors and HMG-CoA reductase inhibitors into single dosage forms has many potential. Presents specific problems. Some HMG-CoA reductase inhibitor compounds are unstable in that they are susceptible to heat, moisture, low pH environments, and light. Some HMG-CoA reductase inhibitors, such as atorvastatin, pravastatin, florastatin, rosuvastatin and cerivastatin, are in the form of hydroxy acids that degrade into lactones in an acidic environment. Other HMG-CoA reductase inhibitors such as lovastatin and simvastatin contain substituents that are easily degraded in acidic environments. When packaged in the form of tablets, powders, granules, or in capsules, HMG-CoA reductase inhibitors are more unstable due to contact with some of the molecules of other components of the dosage form. May be. Since pharmaceutical agent formations such as binders, diluents, anti-adhesive agents, surfactants, etc. may interact adversely with this active ingredient compound, the means of stabilization become an effective pharmaceutical dosage form. Is necessary. For example, US Pat. No. 6,126,971 discloses the addition of stabilizers such as calcium carbonate to stabilize atorvastatin calcium, an HMG-CoA reductase inhibitor. Nevertheless, the means of stabilizing HMG-CoA reductase inhibitors also results in solubilization of CETP inhibitors.

  Accordingly, desirable are dosage forms containing CETP inhibitors and HMG-CoA reductase inhibitors that stabilize HMG-CoA reductase inhibitors and provide good bioavailability of CETP inhibitors.

SUMMARY OF THE INVENTION The present invention provides a unit dosage form comprising (1) an amorphous solid dispersion comprising a CETP inhibitor and an acidic concentrated polymer, and (2) an HMG-CoA reductase inhibitor. Overcoming the shortcomings of the prior art. The amorphous solid dispersion and the HMG-CoA reductase inhibitor are combined together in the dosage form such that the amorphous solid dispersion and the HMG-CoA reductase inhibitor are substantially separated from each other in the dosage form. To be.

  A “unit dosage form” is a CETP inhibitor and HMG-CoA reduction, such that after administration of the unit dosage form to the environment of use, both the CETP inhibitor and the HMG-CoA reductase inhibitor are delivered to the environment of use. A single dosage form containing both enzyme inhibitors is meant. The term “unit dosage form” refers to a single tablet, caplet, pill, capsule, powder, and one or more tablets, caplets, pills, capsules intended to be taken together Means a kit containing a sachet, powder or liquid.

  “Substantially separated from each other” means that a sufficient amount of HMG-CoA reductase inhibitor is sufficient so that the acid-concentrated polymer does not cause unacceptable levels of chemical degradation of the HMG-CoA reductase inhibitor. It means physically separated from the amorphous solid dispersion. Therefore, HMG-CoA reductase inhibitors consist essentially of (1) particles consisting essentially of an amorphous solid dispersion of a CETP inhibitor and an acid-concentrated polymer, and (2) only from HMG-CoA reductase inhibitors. Have improved chemical stability over the formulated mixture of particles. The improved chemical stability of this HMG-CoA reductase inhibitor reduces the fraction of HMG-CoA reductase inhibitor molecules in contact with an amorphous solid dispersion of CETP inhibitor / acid-concentrated polymer It seems to be mainly related to doing. As described below, there are many ways to formulate a unit dosage form in which the amorphous solid dispersion and the HMG-CoA reductase inhibitor are substantially separated from each other; Limiting the fraction of HMG-CoA reductase inhibitor molecules in contact with an amorphous solid dispersion of CETP inhibitor and acidic concentrated polymer.

  For some methods, the separation is macroscopic in nature; that is, the HMG-CoA reductase inhibitor and the amorphous solid dispersion are, for example, in separate layers of the dosage form, resulting in two Only such HMG-CoA reductase inhibitor molecules present at the interface of the layers can contact the amorphous solid dispersion. In addition, separation between the HMG-CoA reductase inhibitor and the amorphous solid dispersion can be obtained by providing a third layer that separates the two compositions. Alternatively, the unit dosage form can be in the form of a kit such that the HMG-CoA reductase inhibitor and the amorphous solid dispersion are in separate compartments within the dosage form.

  For another method, the separation is microscopic in nature; that is, the separation is due solely to one or more intervening molecules. For example, a unit dosage form can comprise a number of relatively large particles or granules containing an amorphous solid dispersion and an HMG-CoA reductase inhibitor. HMG-CoA reductase inhibitor molecules located inside the particle or granule are separated from the amorphous solid dispersion by molecules on the surface of the particle or granule. Alternatively, the amorphous solid dispersion can be in the form of relatively large particles or granules, and the molecules of the acidic concentrated polymer in the amorphous solid dispersion inside the particles or granules It is separated from HMG-CoA reductase inhibitors by molecules on the surface. Alternatively, the particles or granules of the HMG-CoA reductase inhibitor, the particles or granules of the amorphous solid dispersion, or both can be coated with a protective coating so that the HMG-CoA reductase inhibitor and non- A crystalline solid dispersion is isolated. In any case, the HMG-CoA reductase inhibitor and the amorphous solid dispersion are substantially different from each other so that the acidic concentrated polymer does not cause unacceptable levels of chemical degradation of the HMG-CoA reductase inhibitor. Separated.

References in the environment of use refer to the gastrointestinal tract, subcutaneous, intranasal, intraoral, intrathecal, intraocular, intraauricular, subcutaneous space, vagina, arteries of mammals and animals such as humans in particular. And in vitro fluids such as venous blood vessels, or airways or intramuscular tissue, or in vitro of test solutions such as phosphate buffered saline (PBS) or fasted duodenal model (MFD) fluids Can mean any of the environment. A suitable PBS solution is an aqueous solution containing 20 mM sodium phosphate (Na ₂ HPO ₄ ), 47 mM potassium phosphate (KH ₂ PO ₄ ), 87 mM NaCl, and 0.2 mM KCl, adjusted to pH 6.5 with NaOH. is there. A suitable MFD solution is the same PBS solution additionally containing 7.3 mM sodium taurocholate and 1.4 mM 1-palmitoyl-2-oleyl-sn-glycero-3-phosphocholine.

  “Administration” to the environment of use means delivery by feeding or swallowing or other such means to deliver the drug when the in vivo environment of use is the gastrointestinal tract. One skilled in the art will understand that “administering” to another in vivo use environment means contacting the use environment with a composition of the present invention using methods known in the art. See, for example, Remington's “The Science and Practice of Pharmacy” 20th edition (2000). When the environment of use is in vitro, “administration” means the placement or delivery of the dosage form to the in vitro test medium. Release of the drug to the stomach is undesirable, but if release of the drug in the duodenum or small intestine is desired, the use environment is also the duodenum or small intestine. In such cases, “introduction” to the environment of use is the point at which the dosage form exits the stomach and enters the twelve small intestine.

  We know that the bioavailability of CETP inhibitors may be substantially improved by the formation of an amorphous solid dispersion of CETP inhibitor and acidic thickened polymer. Administration of CETP inhibitor in the form of an amorphous solid dispersion containing a thickened polymer substantially increases the concentration of dissolved CETP inhibitor in the use environment compared to administration of CETP inhibitor in crystalline form To do. In particular, the use of certain acidic concentrated polymers results in a substantial improvement in bioavailability.

  However, when the HMG-CoA reductase inhibitor is mixed directly with an amorphous solid dispersion of CETP inhibitor and acidic concentrated polymer and then granulated in a tablet formulation, we have A chemical degradation of the HMG-CoA reductase inhibitor that is greater than that observed with the reductase inhibitor alone is observed. We maintain the dispersion and HMG-CoA reductase inhibitor in a unit dosage form while at the same time substantially physically separating the amorphous solid dispersion from the HMG-CoA reductase inhibitor. The problem of chemical decomposition was solved. We believed that chemical degradation was caused by the transfer of acid-enriched polymer or indirectly acid to the surface of the HMG-CoA reductase inhibitor. Surprisingly, we found that the chemical stability of the HMG-CoA reductase inhibitor in the unit dosage form is different from that of the CETP inhibitor amorphous solid dispersion, separate from the HMG-CoA reductase inhibitor. It was found that the improvement was achieved by granulation. We do not wish to be bound by any particular theory, but granules containing an amorphous solid dispersion and a granulating excipient are compounded with an HMG-CoA reductase inhibitor and then compressed into tablets. The amorphous solid dispersion is substantially separated from the HMG-CoA reductase inhibitor, thereby stabilizing the HMG-CoA reductase inhibitor. Alternatively, another method can be used to separate the amorphous solid dispersion from the HMG-CoA reductase inhibitor. In addition, the presence of the basic nature of the HMG-CoA reductase inhibitor itself, or one or more basic excipients, for example in the form of a basic salt, is caused by the amorphous solid dispersion. It can be used to shield HMG-CoA reductase inhibitors from the acidic environment that is formed.

  The foregoing and other objects, features and advantages of the invention will be more readily understood from a consideration of the following detailed description of the invention when taken in conjunction with the accompanying drawings.

Detailed Description of the Invention The present invention combines a CETP inhibitor and an HMG-CoA reductase inhibitor in a unit dosage form. CETP inhibitors are in the form of an amorphous solid dispersion containing an acidic concentrated polymer. The amorphous solid dispersion is combined with the HMG-CoA reductase inhibitor so that the amorphous solid dispersion and the HMG-CoA reductase inhibitor are substantially separated from each other in the dosage form. Unit dosage forms, amorphous solid dispersions, drugs, excipients, and methods of forming dosage forms are discussed in more detail below.

<Unit dosage form in which CETP inhibitor and HMG-CoA reductase inhibitor are substantially separated>
The unit dosage form of the present invention comprises (1) a CETP inhibitor composition comprising an amorphous solid dispersion containing a CETP inhibitor and an acidic concentrated polymer, and (2) a HMG-CoA reductase inhibitor An HMG-CoA reductase inhibitor composition. These two compositions are combined so that the amorphous solid dispersion and the HMG-CoA reductase inhibitor are substantially separated from each other in the dosage form. The amorphous solid dispersion and the HMG-CoA reductase inhibitor must be substantially physically separated, so that the acid-concentrated polymer has an unacceptable level of chemistry for the HMG-CoA reductase inhibitor. Decomposition does not occur. The resulting unit dosage form has improved chemical stability when compared to a control dosage form in which the amorphous solid dispersion and the HMG-CoA reductase inhibitor are not substantially separated from each other.

  The HMG-CoA reductase inhibitor and the acidic concentrated dispersion polymer are substantially physically separated in the dosage form. This means that the HMG-CoA reductase inhibitor molecular fraction in contact with the acidic concentrated polymer in the amorphous solid dispersion is small enough so that the acidic environment created by the acidic concentrated polymer is , Meaning that it does not lead to unacceptable levels of chemical degradation of HMG-CoA reductase inhibitors. Separation of the HMG-CoA reductase inhibitor and the acidic concentrated polymer results in improved chemical stability of the HMG-CoA reductase inhibitor in the dosage form.

  Several different methods can be used to separate the amorphous solid dispersion and the HMG-CoA reductase inhibitor. In one method, the amorphous solid dispersion is granulated into CETP inhibitor granules with optional granulation excipients and then mixed with the HMG-CoA reductase inhibitor composition. If an acidic thickened polymer is present in the granule, the amount of acidic thickened polymer on the surface of the granule that may come into contact with the HMG-CoA reductase inhibitor composition is smaller than the amorphous solid dispersion particles. Low due to the reduced surface to volume ratio resulting from the use of larger granules. In addition, any granulating excipient reduces the amount of acidic thickened polymer on the outer surface of the granule. As a result, when the granules are mixed with the HMG-CoA reductase inhibitor composition, the HMG-CoA reductase inhibitor and the acidic concentrated polymer are substantially separated, improving the HMG-CoA reductase inhibitor Resulting in improved chemical stability.

  Thus, in one aspect, an amorphous solid dispersion of CETP inhibitor and acidic concentrated polymer, schematically shown as dosage form 10 in FIG. 1, is granulated, followed by an HMG-CoA reductase inhibitor and A unit dosage form to be mixed is provided. Granules 12 containing an amorphous solid dispersion of CETP inhibitor and acidic concentrated polymer and optional granulation excipients are interspersed within HMG-CoA reductase inhibitor composition 14. The amorphous solid dispersion within the granules is substantially separated from the HMG-CoA reductase inhibitor. The dosage form 10 is optionally coated with a conventional coating 16.

  Alternatively, the HMG-CoA reductase inhibitor is granulated with any granulating excipient and mixed with the CETP inhibitor composition. Thus, in another aspect, an HMG-CoA reductase inhibitor is granulated, as shown schematically in dosage form 20 of FIG. 2, followed by an amorphous solid of CETP inhibitor and acidic concentrated polymer. A unit dosage form is provided that is mixed with the dispersion. Granules 24 containing an HMG-CoA reductase inhibitor and optional granulation excipients are interspersed within the CETP inhibitor composition 22. The HMG-CoA reductase inhibitor particles in the granules are substantially separated from the amorphous solid dispersion in the CETP inhibitor composition. The dosage form 20 is optionally coated with a conventional coating 26.

  In another method, the amorphous solid dispersion may be granulated into CETP inhibitor granules by any granulating excipient, and the HMG-CoA reductase inhibitor may be granulated by any granulation Depending on the agent, it may be granulated into HMG-CoA reductase inhibitor granules, and these two granules are blended together. Thus, in another aspect, the unit dosage form comprises a CETP inhibitor mixed with a second granule containing an HMG-CoA reductase inhibitor, as schematically illustrated in dosage form 30 of FIG. A first granule containing an amorphous solid dispersion of an acidic thickened polymer is included. Here, the CETP inhibitor granule 32 is mixed with the HMG-CoA reductase inhibitor granule 34. Surprisingly, the inventors have discovered that the stability of HMG-CoA reductase inhibitors is maintained by mixing these two granules together. In contrast, a composition in which the amorphous solid dispersion, HMG-CoA reductase inhibitor, and other excipients are all granulated together to chemically degrade the HMG-CoA reductase inhibitor. Produce things. The dosage form 30 can optionally be coated with a conventional coating 36.

  In yet another method, the CETP inhibitor composition comprises an amorphous solid dispersion coated with a non-acidic material. This composition is mixed with the HMG-CoA reductase inhibitor composition to prevent the amorphous solid dispersion from contacting the HMG-CoA reductase inhibitor. Alternatively, in order to prevent the amorphous solid dispersion from coming into contact with the HMG-CoA reductase inhibitor, the HMG-CoA reductase inhibitor composition is coated with a non-acidic material and then with the CETP inhibitor composition. Can be mixed. In either case, the coating is thick enough to ensure that the HMG-CoA reductase inhibitor and the amorphous solid dispersion are substantially separated, resulting in improved chemical stability. .

  Thus, in one aspect, a CETP inhibitor composition, such as that schematically illustrated in dosage form 40 of FIG. 4, is coated with a coating and is formulated with an HMG-CoA reductase inhibitor. A unit dosage form containing a solid dispersion is provided. The amorphous solid dispersion 42 is covered with a coating 45. In one embodiment, the amorphous solid dispersion is coated with a non-acidic protective coating. This coating substantially separates the amorphous solid dispersion from the HMG-CoA reductase inhibitor. The coating may be any conventional coating that does not contain acid groups, or other materials that do not adversely interact with either the amorphous solid dispersion or the HMG-CoA reductase inhibitor. The coated amorphous solid dispersion is then mixed with the HMG-CoA reductase inhibitor composition 44. The dosage form 40 may optionally be coated with a conventional coating 46.

  In another aspect, the HMG-CoA reductase inhibitor composition is provided in a unit dosage form containing an HMG-CoA reductase inhibitor coated with a non-acidic coating. The HMG-CoA reductase inhibitor composition is then formulated with an amorphous solid dispersion, as schematically shown in dosage form 50 of FIG. The HMG-CoA reductase inhibitor 54 is coated with a coating 55. The coating substantially separates the amorphous solid dispersion from the HMG-CoA reductase inhibitor. The coating may be any conventional coating that does not contain acid groups, or other materials that do not adversely interact with either the amorphous solid dispersion or the HMG-CoA reductase inhibitor. The coated HMG-CoA reductase inhibitor is then mixed with the amorphous solid dispersion 52. The dosage form 50 may optionally be coated with a conventional coating 56.

  As yet another method, the CETP inhibitor composition and the HMG-CoA reductase inhibitor composition may be formed in discrete regions or volumes of the dosage form, such as discrete layers. Accordingly, in one aspect, a unit dosage form is provided in which the CETP inhibitor composition and the HMG-CoA reductase inhibitor composition are present in separate layers or volumes within the dosage form. In one embodiment, the dosage form is a bilayer tablet schematically illustrated in dosage form 60 of FIG. The dosage form 60 has a first layer 62 composed of a CETP inhibitor composition and a second layer 64 composed of an HMG-CoA reductase inhibitor composition. The dosage form 60 is optionally coated with a conventional coating 66. These layers 62 and 64 can be formed by any conventional method as described below. By separating the CETP inhibitor composition and the HMG-CoA reductase inhibitor composition into two separate layers, the amorphous solid dispersion and the HMG-CoA reductase inhibitor are substantially separated from each other. . This results in an acceptable slow degradation rate of the HMG-CoA reductase inhibitor.

  Another unit dosage embodiment is a three-layer dosage form having three layers. FIG. 7 schematically shows a three-layer dosage form 70 having layers 72, 74 and 78. One or more of layers 72, 74, and 78 can have a CETP inhibitor composition, and one or more of layers 72, 74, and 78 can have a HMG-CoA reductase inhibitor composition. . Trilayer dosage forms are formed by any of the conventional methods described below. Again, by separating the CETP inhibitor composition and the HMG-CoA reductase inhibitor composition into separate layers, the amorphous solid dispersion and the HMG-CoA reductase inhibitor are substantially separated from each other. , Resulting in an acceptable slow degradation rate of HMG-CoA reductase inhibitors. The dosage form 70 is optionally coated with a conventional coating 76.

  In certain embodiments of the three-layer dosage form 70, the layer 78 includes a non-acid barrier layer that separates the CETP inhibitor composition 72 from the HMG-CoA reductase inhibitor composition 74. This barrier layer ensures that the amorphous solid dispersion and the HMG-CoA reductase inhibitor are substantially separated from each other resulting in an acceptable slow degradation rate of the HMG-CoA reductase inhibitor.

  In another embodiment (not shown), the unit dosage form has more than 3 layers. At least one layer is a CETP inhibitor composition and at least one layer is an HMG-CoA reductase inhibitor composition. Optionally, at least one layer is a non-acid barrier layer. These layers are arranged such that the amorphous solid dispersion and the HMG-CoA reductase inhibitor are substantially separated from each other.

  Yet another unit dosage form embodiment is a concentric core dosage form having a central core and an outer layer surrounding the core. FIG. 8 schematically illustrates a dosage form 80 having a central core 82 and a layer 84 surrounding the core 82. The CETP inhibitor composition is in the central core 82 and has an HMG-CoA reductase inhibitor composition in the surrounding layer 84, or the HMG-CoA reductase inhibitor composition is in the central core 82 and Within layer 84 is a CETP inhibitor composition. By separating the CETP inhibitor composition and the HMG-CoA reductase inhibitor composition into separate volumes, the amorphous solid dispersion and the HMG-CoA reductase inhibitor are substantially separated from each other, resulting in Provides an acceptable slow degradation rate for HMG-CoA reductase inhibitors. In order to ensure that the amorphous solid dispersion and the HMG-CoA reductase inhibitor are substantially separated from each other, the central core may optionally be coated with a non-acid protective coating. The dosage form 80 may optionally be coated with a conventional coating 86.

  The unit dosage form may be a tablet, caplet, pill, capsule, powder or other dosage form known in the art. In one embodiment, the CETP inhibitor composition and the HMG-CoA reductase inhibitor composition are formulated together and then compressed into tablets, caplets, pills, or other compression forces known in the art. To the dosage form formed by An example of a suitable tablet is shown in FIGS. 1-8.

  Yet another unit dosage embodiment is a capsule. The CETP inhibitor composition and the HMG-CoA reductase inhibitor composition are mixed and placed in a suitable capsule, such as a hard gelatin capsule or soft gelatin capsule, as is well known in the art (e.g. "See Remington's Pharmaceutical Sciences" (18th edition, 1990)). These compositions are formed such that the amorphous solid dispersion and the HMG-CoA reductase inhibitor are substantially separated in the dosage form. In one embodiment, the CETP inhibitor composition is first granulated and then mixed with the HMG-CoA reductase inhibitor composition, and the mixture is placed in a capsule. In another embodiment, the HMG-CoA reductase inhibitor composition is first granulated and then mixed with the CETP inhibitor composition and the mixture is placed in a capsule. In yet another embodiment, the CETP inhibitor composition is granulated and mixed with the granules of the HMG-CoA reductase inhibitor composition. In yet another embodiment, the CETP inhibitor composition comprises an amorphous solid dispersion coated with a protective coating. The coated amorphous solid dispersion is then mixed with the HMG-CoA reductase inhibitor composition and this mixture is placed in a capsule. In yet another embodiment, the HMG-CoA reductase inhibitor composition comprises coated HMG-CoA reductase inhibitor particles. The coated particles are mixed with a CETP inhibitor composition, and this mixture is placed in a capsule. In yet another embodiment, the HMG-CoA reductase inhibitor composition comprises compressed tablets containing an HMG-CoA reductase inhibitor and optional excipients. The HMG-CoA reductase inhibitor tablet is placed in a capsule with a CETP inhibitor composition. In yet another embodiment, the CETP inhibitor composition comprises a compressed tablet containing an amorphous solid dispersion and optional excipients. CETP inhibitor tablets are placed in capsules with the HMG-CoA reductase inhibitor composition.

  Yet another unit dosage form embodiment is a powder, often referred to in the art as a sachet or an oral powder for reconstitution (OPC). The CETP inhibitor composition and the HMG-CoA reductase inhibitor composition are mixed and placed in a suitable container such as a pouch, bottle, box, bag or other container known in the art. These compositions are formed such that the amorphous solid dispersion and the HMG-CoA reductase inhibitor are substantially separated in the dosage form as previously described. The powder dosage form can then be dried and mixed with the liquid prior to administration to form a paste, suspension or slurry.

  Yet another unit dosage form embodiment is a kit comprising two separate compositions: (1) comprising an amorphous solid dispersion containing a CETP inhibitor and an acidic concentrated polymer; 2) Including HMG-CoA reductase inhibitor. The kit is designed such that the HMG-CoA reductase inhibitor and the amorphous solid dispersion are substantially separated. The kit comprises means comprising a separate composition, such as a split bottle or split foil packet; however, the separate composition may be contained in a single undivided container. Typically, the kit will include instructions for administration of the individual components.

<Chemical stability>
A dosage form in which the amorphous solid dispersion and the HMG-CoA reductase inhibitor are substantially separated from each other exhibits an acceptable slow degradation rate of the HMG-CoA reductase inhibitor in the dosage form. The compositions and dosage forms of the present invention comprise an amorphous solid dispersion and an equivalent amount of amorphous solid dispersion and HMG-CoA reductase inhibitor that are not substantially separated, as described in detail below. Compared to a control composition consisting of an HMG-CoA reductase inhibitor, it provides improved chemical stability of the HMG-CoA reductase inhibitor.

  In general, degradation of HMG-CoA reductase inhibitors can be measured using any of the conventional methods for measuring the potency or purity of drugs in pharmaceutical compositions. For example, the amount of active HMG-CoA reductase inhibitor present in the composition can be initially measured using high performance liquid chromatography (HPLC) or other analytical techniques known in the art. Alternatively, the amount of HMG-CoA reductase inhibitor initially present can be calculated from the amount of drug present in the composition. The efficacy of the composition is then measured after storage for an appropriate period under controlled temperature and humidity conditions. A decrease in efficacy indicates that a chemical reaction occurs, leading to a decrease in the amount of active drug present in the composition, which is an indication of poor chemical stability.

  Another method used to assess chemical stability is to analyze the rate of increase in the amount of drug degradation (s) in the composition, which is an indicator of the response of the HMG-CoA reductase inhibitor. Let's go. HPLC or other analytical techniques can be used to determine the concentration of drug degradation product (s) in the composition. The amount of degradation product (s) is measured before and after storage under controlled storage conditions. The increase in drug degradation products can be used to determine the amount of decrease in "% drug purity", defined as the total amount of drug present divided by the amount of drug initially present, multiplied by 100 . Thus,% drug purity can be calculated as follows:

  When drug purity is calculated as the total amount of impurities, the first drug present in wt% is equal to 100 wt% minus the total wt% of the first impurity, and the total drug present is % Drug purity can be calculated by assuming that it is equal to 100 wt% minus the wt% of total impurities after storage, ie at any later time point. The calculation method of this% drug purity is the following formula.

  The rate at which drug degradation occurs generally depends on storage conditions. When an HMG-CoA reductase inhibitor is formulated in the composition of the present invention, this may be for months or years at ambient temperature and humidity conditions (eg, relative humidity (RH) 20% to 60%). It must be stable for a long time. However, to process the test quickly, the storage conditions can use elevated temperatures and / or humidity to mimic the relatively long storage time at ambient conditions. Depending on the reactivity of the drug and storage conditions, the storage period can vary from days to weeks or months.

  The "degradation degree" of a drug after storage is determined by subtracting the final% drug purity (determined by measuring either the decrease in drug present or the increase in impurities present) from the initial% drug purity Is done. For example, a sample of a composition that initially contains 100 mg HMG-CoA reductase inhibitor and has no measurable impurities has an initial% drug purity of 100 wt%. After storage, if the amount of HMG-CoA reductase inhibitor in the sample is reduced to 95 mg, the final% drug purity is 95 wt%, and the degree of degradation is 100 wt% minus 95 wt%, ie 5 wt%. Alternatively, if it was found to have 1 mg of impurities initially present in 100 mg of HMG-CoA reductase inhibitor, the initial% drug purity would be 99 wt%. If the total amount of impurities present after storage increases to 6 wt%, the final% drug purity will be 94 wt% and the degree of degradation will be 99 wt% minus 94 wt%, ie 5 wt%.

  Alternatively, the degree of degradation can be determined by subtracting the amount of degradation of one or more particular drugs initially present from the amount of degradation of the particular drug present after storage. Such a measurement is useful when there are several drug degradation products for which only one or several are of concern. For example, if the HMG-CoA reductase inhibitor initially contains a specific degradation product with a concentration of 1 wt%, and the degradation product concentration is 6 wt% after storage, the degree of degradation is 6 wt% minus 1 wt%, ie 5 wt% .

  The relative improvement in chemical stability of the HMG-CoA reductase inhibitor in the test composition is the same as the degree of degradation of the HMG-CoA reductase inhibitor in the control composition under the same storage conditions and at the same storage period. This can be determined by obtaining the ratio of the degree of degradation of the HMG-CoA reductase inhibitor in the composition. The test composition is simply an amorphous amorphous form of CETP inhibitor and acid-concentrated polymer whose unit dosage form is prepared such that the amorphous solid dispersion and the HMG-CoA reductase inhibitor are substantially separated from each other. Solid dispersion, HMG-CoA reductase inhibitor, and any additional excipient composition. The control composition is simply combined in one step with the amorphous solid dispersion, HMG-CoA reductase inhibitor and any additional excipients, then compressed to form a slug A composition of an amorphous solid dispersion of the same amount of CETP inhibitor and acidic concentrated polymer, an HMG-CoA reductase inhibitor, and any additional excipients. To facilitate testing of the control composition, the blob is broken into smaller granules. For example, if the degree of degradation of the HMG-CoA reductase inhibitor in the test composition is 1 wt% and the degree of degradation of the HMG-CoA reductase inhibitor in the control composition is 5 wt%, the relative improvement is 5wt% / 1wt%, which is equal to 5.0. For compositions and dosage forms in which the HMG-CoA reductase inhibitor and the amorphous solid dispersion are substantially separated from each other, the relative improvement is at least 1.1. Preferably, this relative improvement is at least 1.25, more preferably at least 2.0, and even more preferably at least 3.0, more preferably at least 5.0. In fact, some compositions of the present invention may achieve a relative improvement of greater than 20.

  Depending on the acid-sensitivity of the HMG-CoA reductase inhibitor, the specific acid-concentrated polymer used in the amorphous solid dispersion, and the ratio of HMG-CoA reductase inhibitor to polymer in the composition Thus, specific storage conditions and storage periods may be conveniently selected. A shorter shelf life can be used if the HMG-CoA reductase inhibitor is particularly acid-sensitive or if the composition has a low ratio of HMG-CoA reductase inhibitor to polymer. If the degradation rate is linear, the relative improvement will be independent of the shelf life. However, when the degradation rate is non-linear under controlled storage conditions, the stability test used to compare the test composition to the control composition is a measure of the degree of degradation accurately measured. It is preferred that it be selected to be sufficiently large. Typically, the time period is selected so that a degree of degradation of the control composition of at least 0.1 wt% to 0.2 wt% is observed. However, this period is as long as the ratio of HMG-CoA reductase inhibitor to polymer does not vary substantially. Typically, the period is such that the observed degree of degradation of the test composition is less than 50 wt%, preferably less than 20 wt%. If the degradation rate in the control composition is relatively slow, the test may be run long enough to make a meaningful comparison of the stability of the test composition with the control composition under controlled storage conditions. preferable.

  The stability test used to test whether the composition or dosage form meets the previously described chemical stability criteria is the 40 ° C. and relative humidity (RH) of the test and control dispersions. Storage for 6 months at 75% or 3 months at 50 ° C and 75% RH. Relative improvement begins to become apparent within a relatively short period of time, such as 3-5 days, and shorter storage times may be used for some highly acid-sensitive HMG-CoA reductase inhibitors it can. When comparing dispersions under storage conditions close to ambient conditions such as 30 ° C. and 60% RH, the storage period may need to be several months or up to 2 years.

  In addition, a composition containing an HMG-CoA reductase inhibitor and an amorphous solid dispersion has a degree of degradation when the HMG-CoA reductase inhibitor is stored at 40 ° C. and 75% RH for 6 months. Has less than about 5 wt%, more preferably less than about 2 wt%, even more preferably less than about 0.5 wt%, and most preferably less than about 0.1 wt%, or stored for 1 year at 30 ° C and 60% RH In some cases, it is preferable to produce a chemical stability that is less than about 5 wt%, more preferably less than about 2 wt%, even more preferably less than about 0.5 wt%, more preferably less than about 0.1 wt%. However, the compositions of the present invention may have a degree of degradation that is much greater than the preferred value, as long as the amorphous solid dispersion achieves an improvement over the control composition as explained above. .

<Cholesteryl ester transfer protein inhibitor>
The CETP inhibitor may be any compound capable of inhibiting cholesteryl ester transfer protein. Amorphous solid dispersions are particularly useful for CETP inhibitors with sufficiently low water solubility, low bioavailability or slow absorption rate, as it is desirable to increase their concentration in the aqueous environment of use . CETP inhibitors are typically `` slightly soluble in water '', which means that CETP inhibitors are about 1-2 mg / mL at physiologically relevant pH (e.g., pH 1-8) and about 22 ° C. It is meant to indicate a minimum solubility in water such that it is less than. Many CETP inhibitors are “substantially insoluble in water,” which means that CETP inhibitors are about 0.01 mg / mL at physiologically relevant pH (e.g., pH 1-8) and about 22 ° C. Or a minimum solubility in water that is less than 10 μg / ml). (Unless otherwise noted, the water solubility reference herein and the “claims” is determined at about 22 ° C.) Compositions of the present invention reduce CETP inhibitor solubility. As such, CETP inhibitors with a solubility of less than about 10 μg / mL are preferred, with CETP inhibitors with a solubility of less than about 1 μg / mL being more preferred. Many CETP inhibitors have even lower solubility (some are even less than 0.1 μg / mL) and are sufficiently bioavailable upon oral administration at effective plasma concentrations that should be reached at practical doses Requires dramatic enrichment.

  In general, CETP inhibitors have a dose-to-water solubility ratio greater than about 100 mL, where the solubility (mg / mL) is any physiological, including USP mimic stomach and small intestinal buffer. The lowest value observed in the relevant aqueous solution (eg, having a pH value of 1-8), and the dosage is in mg. The compositions of the present invention, as described above, find greater utility as CETP inhibitor solubility decreases and dosage increases. Thus, compositions are preferred as the dose-to-solubility ratio increases, so that the dose-to-solubility ratio is preferably greater than 1000 mL and the dose-to-solubility ratio is greater than about 5000 ml. More preferred. The dose-to-solubility ratio can be determined by dividing the dose (mg) by the solubility in water (mg / ml).

  Oral delivery of many CETP inhibitors is particularly difficult because their water solubility is usually very low, typically less than 2 μg / ml, sometimes less than 0.1 μg / ml. Such low solubility is a direct result of certain structural features of the species that bind to CETP and thus act as CETP inhibitors. This low solubility is mainly due to the hydrophobic nature of CETP inhibitors. LogP, defined as the base 10 logarithm of the ratio of drug solubility in octanol to drug solubility in water, is a widely accepted measure of hydrophobicity. LogP is measured experimentally or calculated using methods known in the art. The calculated LogP values are often referred to as AlogP, ClogP, and MlogP depending on the calculation method. Typical LogP values for CETP inhibitors are greater than 4 and often greater than 5. Thus, the hydrophobic and insoluble nature of CETP inhibitors as a class poses particular challenges for oral delivery. Achieving therapeutic drug levels in the blood by oral administration of a practical amount of drug generally requires a large increase in drug concentration in the digestive fluid, resulting in a large increase in bioavailability. To achieve the desired blood level, the increase in drug concentration in such digestive fluid is typically at least about 10-fold, sometimes at least about 50-fold, or even at least about 200-fold. is required. Surprisingly, the amorphous solid dispersions of the present invention have proven to have the necessary large increase in drug concentration and bioavailability.

  In contrast to common knowledge, the relative increase in aqueous concentration and bioavailability provided by amorphous solid dispersions generally improves for CETP inhibitors as solubility decreases and hydrophobicity increases. In fact, the inventors recognize these subclasses of CETP inhibitors that are essentially insoluble in water, highly hydrophobic, and characterized by a set of physical properties. This subclass exhibits a dramatic increase in aqueous concentration and bioavailability when formulated using amorphous solid dispersions.

  The first property of this subclass of essentially insoluble and hydrophobic CETP inhibitors is very low water solubility. Very low water solubility means that the minimum solubility in water at physiologically relevant pH (pH 1-8) is less than about 10 μg / ml, preferably less than about 1 μg / ml.

  The second characteristic is a very high dose-to-solubility ratio. Very low solubility often leads to low or slow absorption of the drug from the gastrointestinal fluid when the drug is administered orally in the normal manner. For drugs with very low solubility, low absorption generally begins to become increasingly difficult as dose (amount of drug given orally) increases. Thus, the second property of this subclass of essentially insoluble, hydrophobic CETP inhibitors is a very high dose (mg) to solubility (mg / ml) ratio (ml). “Very high dose-to-solubility ratio” means that the dose-to-solubility ratio has a value of at least 1000 ml, preferably at least 5,000 ml, more preferably at least 10,000 ml.

  A third feature of this subclass of essentially insoluble and hydrophobic CETP inhibitors is that they are extremely hydrophobic. Extremely hydrophobic means that the LogP of the drug has a value of at least 4.0, preferably at least 5.0, more preferably at least 5.5.

  A fourth characteristic of this subclass of essentially insoluble CETP inhibitors is that they have a low melting point. In general, this subclass of drugs will have a melting point of about 150 ° C. or lower, preferably about 140 ° C. or lower.

  Mainly as a result of some or all of these four properties, this subclass of CETP inhibitors typically has very low absolute bioavailability. Specifically, the absolute bioavailability of this subclass of drugs when administered orally in their undispersed state is less than about 10%, more frequently less than about 5%.

  With respect to this subclass of CETP inhibitors, when dispersed in an amorphous solid dispersion, the CETP inhibitor is preferably at least substantially completely if not at least substantially amorphous as described below. Must be amorphous. In addition, the amorphous solid dispersion must be substantially homogeneous. As discussed below, such dispersions can be used in mechanical processes such as grinding and extrusion; melting processes such as melting, melt-extrusion, and melt-solidification; and no-solvent precipitation, spray coating, and Made by a solvent process such as spray-drying. When prepared in this manner, this class of essentially insoluble, hydrophobic CETP inhibitors often exhibits a dramatic increase in aqueous concentration and bioavailability in the environment of use when administered orally. The degree of increase depends on the specific thickening polymer, but when a preferred thickening polymer (as described below) is used, such a composition is essentially insoluble and hydrophobic. Maximum drug in an aqueous use environment, such that it is at least about 50-fold, preferably at least about 200-fold the equivalent concentration of a control composition containing an equal amount of sex CETP inhibitor but no concentrated polymer Provide concentration (MDC). Similarly, these compositions contain an equal amount of drug in an aqueous use environment for any period of at least 90 minutes between the time of introduction into the use environment and about 270 minutes after introduction of the use environment. Also shown is the area under the concentration versus time curve (AUC) that is at least about 25-fold, preferably at least about 100-fold that of the control composition without the concentrated polymer.

  In the following, those “pharmaceutically acceptable forms” are defined as pharmaceuticals, including stereoisomers, stereoisomer mixtures, enantiomers, solvates, hydrates, isomorphs, polymorphs, salt forms and prodrugs. It means either an acceptable derivative or a variant.

  One class of CETP inhibitors that find utility in the present invention is the formula I

Oxy-substituted 4-carboxyamino-2-methyl-1,2,3,4-tetrahydroquinolines and their pharmaceutically acceptable forms having the formula:
[Wherein R _I-1 is hydrogen, Y _I , W _I -X _I , W _I -Y _I ;
Where W _I is carbonyl, thiocarbonyl, sulfinyl or sulfonyl;
X _I is -OY _I , -SY _I , -N (H) -Y _I or -N (Y _I ) ₂ ;
Where Y _I is independently Z _I for each occurrence, or is a fully saturated, partially unsaturated or fully unsaturated 1-10 membered linear or branched carbon chain Carbons other than those bonded here may optionally be substituted with one or two heteroatoms independently selected from oxygen, sulfur and nitrogen, and the carbons may optionally be independent of halogen. Mono-, di- or tri-substituted, the carbon optionally mono-substituted by hydroxy, the carbon optionally mono-substituted by oxo and the sulfur optionally mono- or di-substituted by oxo. The nitrogen is optionally mono- or di-substituted by oxo and the carbon chain is optionally mono-substituted by Z _I ;
Where Z _I is a partially saturated, fully saturated or fully unsaturated 3-8 membered ring optionally having 1 to 4 heteroatoms independently selected from oxygen, sulfur and nitrogen. Two fused partially saturated, fully saturated or fully unsaturated, optionally having 1 to 4 heteroatoms independently selected from nitrogen, sulfur and oxygen A bicyclic ring consisting of three to six members of
Where the Z _I substituent is optionally halogen, (C ₂ -C ₆ ) alkenyl, (C ₁ -C ₆ ) alkyl, hydroxy, (C ₁ -C ₆ ) alkoxy, (C ₁ -C ₄ ) alkylthio , Amino, nitro, cyano, oxo, carboxyl, (C ₁ -C ₆ ) alkyloxycarbonyl, mono-N- or di-N, N- (C ₁ -C ₆ ) alkylamino independently mono-, di- -Or tri-substituted, wherein the (C ₁ -C ₆ ) alkyl substituent is optionally independently halogen, hydroxy, (C ₁ -C ₆ ) alkoxy, (C ₁ -C ₄ ) alkylthio, amino , Nitro, cyano, oxo, carboxyl, (C ₁ -C ₆ ) alkyloxycarbonyl, mono-N- or di-N, N- (C ₁ -C ₆ ) alkylamino mono-, di- or tri-substituted And the (C ₁ -C ₆ ) alkyl substituent is also optionally substituted with 1 to 9 fluorines;
R _I-3 is hydrogen or Q _I ;
Where Q _I is a fully saturated, partially unsaturated or fully unsaturated 1-6 membered straight or branched carbon chain, where the carbons other than the carbons attached are Optionally substituted with one heteroatom independently selected from oxygen, sulfur and nitrogen, and the carbon is optionally mono-, di- or tri-substituted independently with halogen, the carbon Optionally mono-substituted by hydroxy, the carbon optionally mono-substituted by oxo, the sulfur optionally mono- or di-substituted by oxo, and the nitrogen optionally mono- or di-substituted by oxo And the carbon chain is optionally mono-substituted by V _I ;
Where V _I is a partially saturated, fully saturated or fully unsaturated 3-8 membered ring optionally having 1 to 4 heteroatoms independently selected from oxygen, sulfur and nitrogen. Two fused partially saturated, fully saturated or fully, optionally having 1 to 4 heteroatoms optionally selected independently from nitrogen, sulfur and oxygen A bicyclic ring consisting of an unsaturated 3- to 6-membered ring;
Wherein said V _I substituent is halogen optionally, (C ₁ -C ₆₎ alkyl, (C ₂ -C ₆₎ alkenyl, hydroxy, (C ₁ -C ₆₎ alkoxy, (C ₁ -C ₄₎ Alkylthio, amino, nitro, cyano, oxo, carbamoyl, mono-N- or di-N, N- (C ₁ -C ₆ ) alkylcarbamoyl, carboxyl, (C ₁ -C ₆ ) alkyloxycarbonyl, mono-N- Or di-N, N- (C ₁ -C ₆ ) alkylamino independently mono-, di-, tri- or tetra-substituted, wherein the (C ₁ -C ₆ ) alkyl or (C _2- C ₆ ) alkenyl substituents are optionally independently hydroxy, (C ₁ -C ₆ ) alkoxy, (C ₁ -C ₄ ) alkylthio, amino, nitro, cyano, oxo, carboxyl, (C ₁ -C ₆ ) Alkyloxycarbonyl, mono-N- or di-N, N- (C ₁ -C ₆ ) alkylamino mono-, di- or tri-substituted, said (C ₁ -C ₆ ) alkyl or (C _2- C ₆ ) alkenyl substituents are also optionally Substituted with 1 to 9 fluorines;
R _I is Q _I-1 or V _I-1 ,
Where Q _I-1 is a fully saturated, partially unsaturated or fully unsaturated 1 to 6 membered straight or branched carbon chain, where the carbon other than the carbon attached May be optionally substituted with one heteroatom selected from oxygen, sulfur and nitrogen, and the carbon is optionally mono-, di- or tri-substituted independently by halogen, the carbon being optional The carbon is mono-substituted by oxo, the sulfur is optionally mono- or di-substituted by oxo, the nitrogen is optionally mono- or di-substituted by oxo, and The carbon chain is optionally mono-substituted by V _I-1 ;
Where V _I-1 is a partially saturated, fully saturated or fully unsaturated 3-6 membered optionally having 1-2 heteroatoms independently selected from oxygen, sulfur and nitrogen. The ring of
Wherein the V _I-1 substituent is optionally halogen, (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkoxy, amino, nitro, cyano, (C ₁ -C ₆ ) alkyloxycarbonyl Mono-N- or di-N, N- (C ₁ -C ₆ ) alkylamino independently mono-, di-, tri- or tetra-substituted, wherein said (C ₁ -C ₆ ) alkyl The substituent is optionally mono-substituted by oxo and the (C ₁ -C ₆ ) alkyl substituent is optionally substituted by 1 to 9 fluorines;
Where R _I-3 must either contain V _I or R _I-4 must contain V _I-1 ; and R _I-5 , R _I-6 , R _I-7 and R _I-8 are each independently hydrogen, hydroxy or oxy, where the oxy is substituted by T _I or is partially saturated, fully saturated or fully unsaturated 1 to 12-membered straight or branched carbon chain, wherein the carbons other than the bonded carbon are 1 or 2 heteroatoms optionally selected independently from oxygen, sulfur and nitrogen. As well as the carbon is optionally mono-, di- or tri-substituted independently by halogen, the carbon is optionally mono-substituted by hydroxy, and the carbon is optionally mono-substituted by oxo. The sulfur is optionally mono- or di-substituted by oxo, the nitrogen is optionally mono- or di-substituted by oxo, and Is substituted - A by a carbon chain is optionally T _I;
Where T _I is a partially saturated, fully saturated or fully unsaturated 3-8 membered ring optionally having 1 to 4 heteroatoms independently selected from oxygen, sulfur and nitrogen. Two fused partially saturated, fully saturated or fully unsaturated, optionally having 1 to 4 heteroatoms independently selected from nitrogen, sulfur and oxygen A bicyclic ring consisting of three to six members of
Where the T _I substituent is optionally halogen, (C ₁ -C ₆ ) alkyl, (C ₂ -C ₆ ) alkenyl, hydroxy, (C ₁ -C ₆ ) alkoxy, (C ₁ -C ₆ ) alkylthio , Amino, nitro, cyano, oxo, carboxy, (C ₁ -C ₆ ) alkyloxycarbonyl, mono-N- or di-N, N- (C ₁ -C ₆ ) alkylamino independently mono-, di- -Or tri-substituted, wherein the (C ₁ -C ₆ ) alkyl substituent is optionally hydroxy, (C ₁ -C ₆ ) alkoxy, (C ₁ -C ₄ ) alkylthio, amino, nitro, cyano , Oxo, carboxy, (C ₁ -C ₆ ) alkyloxycarbonyl, mono-N- or di-N, N- (C ₁ -C ₆ ) alkylamino independently mono-, di-, or tri-substituted And the (C ₁ -C ₆ ) alkyl substituent is also optionally substituted with 1 to 9 fluorines. ].

  Compounds of formula I are disclosed in US Pat. No. 6,140,342, assigned to the assignee of the present invention, the complete disclosure of which is hereby incorporated by reference.

In a preferred embodiment, the CETP inhibitor is selected from one of the following compounds of formula I:
[2R, 4S] 4-[(3,5-Dichloro-benzyl) -methoxycarbonyl-amino] -6,7-dimethoxy-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester ;
[2R, 4S] 4-[(3,5-Dinitro-benzyl) -methoxycarbonyl-amino] -6,7-dimethoxy-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester ;
[2R, 4S] 4-[(2,6-Dichloro-pyridin-4-ylmethyl) -methoxycarbonyl-amino] -6,7-dimethoxy-2-methyl-3,4-dihydro-2H-quinoline-1- Carboxylic acid ethyl ester;
[2R, 4S] 4-[(3,5-Bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -6,7-dimethoxy-2-methyl-3,4-dihydro-2H-quinoline-1- Carboxylic acid ethyl ester;
[2R, 4S] 4-[(3,5-Bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -6-methoxy-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylic acid Ethyl ester;
[2R, 4S] 4-[(3,5-Bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -7-methoxy-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylic acid Ethyl ester;
[2R, 4S] 4-[(3,5-Bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -6,7-dimethoxy-2-methyl-3,4-dihydro-2H-quinoline-1- Carboxylic acid isopropyl ester;
[2R, 4S] 4-[(3,5-Bis-trifluoromethyl-benzyl) -ethoxycarbonyl-amino] -6,7-dimethoxy-2-methyl-3,4-dihydro-2H-quinoline-1- Carboxylic acid ethyl ester;
[2R, 4S] 4-[(3,5-Bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -6,7-dimethoxy-2-methyl-3,4-dihydro-2H-quinoline-1- Carboxylic acid 2,2,2-trifluoro-ethyl ester;
[2R, 4S] 4-[(3,5-Bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -6,7-dimethoxy-2-methyl-3,4-dihydro-2H-quinoline-1- Carboxylic acid propyl ester;
[2R, 4S] 4-[(3,5-Bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -6,7-dimethoxy-2-methyl-3,4-dihydro-2H-quinoline-1- Carboxylic acid t-butyl ester;
[2R, 4S] 4-[(3,5-Bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -2-methyl-6-trifluoromethoxy-3,4-dihydro-2H-quinoline-1- Carboxylic acid ethyl ester;
[2R, 4S] (3,5-Bis-trifluoromethyl-benzyl)-(1-butyryl-6,7-dimethoxy-2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl) -Carbamic acid methyl ester;
[2R, 4S] (3,5-Bis-trifluoromethyl-benzyl)-(1-butyl-6,7-dimethoxy-2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl) -Carbamic acid methyl ester;
[2R, 4S] (3,5-Bis-trifluoromethyl-benzyl)-[1- (2-ethyl-butyl) -6,7-dimethoxy-2-methyl-1,2,3,4-tetrahydro- Quinolin-4-yl] -carbamic acid methyl ester, hydrochloride.

  Another class of CETP inhibitors that have found utility according to the present invention is represented by the formula II

Consisting of 4-carboxyamino-2-methyl-1,2,3,4-tetrahydroquinoline and their pharmaceutically acceptable forms having:
[Wherein R _II-1 is hydrogen, Y _II , W _II -X _II , W _II -Y _II ;
Where W _II is carbonyl, thiocarbonyl, sulfinyl or sulfonyl;
X _II is -OY _II , -SY _II , -N (H) -Y _II or -N- (Y _II ) ₂ ;
Where Y _II is independently for each occurrence Z _II , or a fully saturated, partially unsaturated or fully unsaturated 1-10 membered linear or branched carbon chain, where Carbons other than the carbons to which they are attached may optionally be substituted with 1 or 2 heteroatoms independently selected from oxygen, sulfur and nitrogen, and the carbons may optionally be independently Di- or tri-substituted, the carbon is optionally mono-substituted independently by hydroxy, the carbon is optionally mono-substituted by oxo, and the sulfur is optionally mono- or di-substituted by oxo. The nitrogen is optionally mono- or di-substituted by oxo and the carbon chain is optionally mono-substituted by Z _II ;
Z _II is a partially saturated, fully saturated or fully unsaturated 3- to 12-membered ring optionally having 1 to 4 heteroatoms independently selected from oxygen, sulfur and nitrogen Or, independently, two fused partially saturated, fully saturated or fully unsaturated, optionally having 1 to 4 heteroatoms independently selected from nitrogen, sulfur and oxygen. A bicyclic ring consisting of a saturated 3-6 membered ring;
Where the Z _II substituent is optionally halogen, (C ₂ -C ₆ ) alkenyl, (C ₁ -C ₆ ) alkyl, hydroxy, (C ₁ -C ₆ ) alkoxy, (C ₁ -C ₄ ) alkylthio , Amino, nitro, cyano, oxo, carboxy, (C ₁ -C ₆ ) alkyloxycarbonyl, mono-N- or di-N, N- (C ₁ -C ₆ ) alkylamino independently mono-, di- -Or tri-substituted, wherein the (C ₁ -C ₆ ) alkyl substituent is optionally independently halogen, hydroxy, (C ₁ -C ₆ ) alkoxy, (C ₁ -C ₄ ) alkylthio, Amino, nitro, cyano, oxo, carboxyl, (C ₁ -C ₆ ) alkyloxycarbonyl, mono-N- or di-N, N- (C ₁ -C ₆ ) alkylamino mono-, di- or tri- Substituted, the (C ₁ -C ₆ ) alkyl is also optionally substituted with 1 to 9 fluorines;
R _II-3 is hydrogen or Q _II ;
Where Q _II is a fully saturated, partially unsaturated or fully unsaturated 1-6 membered straight or branched carbon chain, where the carbons other than the carbons attached are Optionally substituted with one heteroatom selected from oxygen, sulfur and nitrogen, and the carbon is optionally mono-, di- or tri-substituted independently by halogen, and the carbon is optionally hydroxy The carbon is optionally mono-substituted by oxo, the sulfur is optionally mono- or di-substituted by oxo, the nitrogen is optionally mono- or di-substituted by oxo, and The carbon chain is optionally mono-substituted by V _II ;
Where V _II is a partially saturated, fully saturated or fully unsaturated 3-12 membered ring optionally having 1 to 4 heteroatoms independently selected from oxygen, sulfur and nitrogen. Two fused partially saturated, fully saturated or fully unsaturated, optionally having 1 to 4 heteroatoms independently selected from nitrogen, sulfur and oxygen A bicyclic ring consisting of three to six members of
Wherein the V _II substituent is optionally halogen, (C ₁ -C ₆ ) alkyl, (C ₂ -C ₆ ) alkenyl, hydroxy, (C ₁ -C ₆ ) alkoxy, (C ₁ -C ₆ ) Alkylthio, amino, nitro, cyano, oxo, carboxamoyl, mono-N- or di-N, N- (C ₁ -C ₆ ) carboxamoyl, carboxy, (C ₁ -C ₆ ) alkyloxycarbonyl, mono-N- or Di-N, N- (C ₁ -C ₆ ) alkylamino is independently mono-, di-, tri- or tetra-substituted, wherein the (C ₁ -C ₆ ) alkyl or (C ₂ -C ₆₎ alkenyl substituents are optionally hydroxy, (C ₁ -C ₆₎ alkoxy, (C ₁ -C ₄₎ alkylthio, amino, nitro, cyano, oxo, carboxy, (C ₁ -C ₆₎ alkyloxycarbonyl, Mono-N- or di-N, N- (C ₁ -C ₆ ) alkylamino mono-, di- or tri-substituted, or the (C ₁ -C ₆ ) alkyl or (C _2- C ₆ ) alkenyl substituent is optionally Substituted with 1 to 9 fluorines;
R _II-4 is Q _II or V _II-1 .
Where Q _II-1 is a fully saturated, partially unsaturated or fully unsaturated 1-6 membered straight or branched carbon chain, where the carbon other than the carbon attached to it. May be optionally substituted with one heteroatom selected from oxygen, sulfur and nitrogen, and the carbon is optionally mono-, di- or tri-substituted independently by halogen, the carbon being optional Is optionally mono-substituted by hydroxy, the carbon is mono-substituted by oxo, the sulfur is optionally mono- or di-substituted by oxo, and the nitrogen is optionally mono- or di-substituted by oxo. And the carbon chain is optionally mono-substituted by V _II-1 ;
Where V _II-1 is a partially saturated, fully saturated or fully unsaturated 3-6 membered optionally having 1-2 heteroatoms independently selected from oxygen, sulfur and nitrogen A ring of
Wherein the V _II-1 substituent is halogen, (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkoxy, amino, nitro, cyano, (C ₁ -C ₆ ) alkyloxycarbonyl, mono- N- or di-N, N- (C ₁ -C ₆ ) alkylamino, wherein the (C ₁ -C ₆ ) alkyl substituent is optionally mono-substituted by oxo and the (C _1- C ₆₎ alkyl substituent is substituted by 1 to 9 fluorine optionally;
Where the R _II-3 substituent must either contain V _II or R _II-4 must contain V _II-1 ; and
R _II-5 , R _II-6 , R _II-7 and R _II-8 are each independently hydrogen, a bond, nitro or halogen, wherein the bond is substituted by T _II or Substituted by a partially saturated, fully saturated or fully unsaturated (C ₁ -C ₁₂ ) linear or branched carbon chain, where the carbon is optionally independently selected from oxygen, sulfur and nitrogen Substituted by one heteroatom, the carbon optionally mono-, di- or tri-substituted independently by halogen, the carbon optionally mono-substituted by hydroxy, the carbon optionally by oxo Mono-substituted, the sulfur is optionally mono- or di-substituted by oxo, the nitrogen is optionally mono- or di-substituted by oxo, and the carbon is optionally mono-substituted by T _II ;
Wherein T _II is a partially saturated, fully saturated or fully unsaturated 3-12 membered having 1 to 4 heteroatoms optionally selected independently from oxygen, sulfur and nitrogen. Two fused partially saturated, fully saturated or fully ring, or independently viewed, optionally having 1 to 4 heteroatoms selected from nitrogen, sulfur and oxygen A bicyclic ring consisting of a fully unsaturated 3-6 membered ring;
Wherein the T _II substituent is optionally independently halogen, (C ₁ -C ₆ ) alkyl, (C ₂ -C ₆ ) alkenyl, hydroxy, (C ₁ -C ₆ ) alkoxy, (C ₁ -C ₄ ) alkylthio, amino, nitro, cyano, oxo, carboxy, (C ₁ -C ₆ ) alkyloxycarbonyl, mono-N- or di-N, N- (C ₁ -C ₆ ) alkylamino mono-, di- -Or tri-substituted, wherein the (C ₁ -C ₆ ) alkyl substituent is optionally hydroxy, (C ₁ -C ₆ ) alkoxy, (C ₁ -C ₄ ) alkylthio, amino, nitro, cyano , Oxo, carboxy, (C ₁ -C ₆ ) alkyloxycarbonyl, mono-N- or di-N, N- (C ₁ -C ₆ ) alkylamino, mono-, di- or tri-substituted, (C ₁ -C ₆ ) alkyl substituents are also optionally substituted with 1 to 9 fluorines; provided that at least one of R _II-5 , R _II-6 , R _II-7 and R _II-8 Substituents are not hydrogen and via oxy And is not linked to the quinoline moiety. ].

  The compound of formula II is disclosed in US Pat. No. 6,147,090 assigned to the assignee of the present invention, the disclosure of which is fully incorporated herein by reference.

In a preferred embodiment, the CETP inhibitor is selected from the following compounds of formula II:
[2R, 4S] 4-[(3,5-Bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -2-methyl-7-trifluoromethyl-3,4-dihydro-2H-quinoline-1- Carboxylic acid ethyl ester;
[2R, 4S] 4-[(3,5-Bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -7-chloro-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylic acid Ethyl ester;
[2R, 4S] 4-[(3,5-Bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -6-chloro-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylic acid Ethyl ester;
[2R, 4S] 4-[(3,5-Bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -2,6,7-trimethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid Ethyl ester
[2R, 4S] 4-[(3,5-Bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -6,7-diethyl-2-methyl-3,4-dihydro-2H-quinoline-1- Carboxylate ethyl ester;
[2R, 4S] 4-[(3,5-Bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -6-ethyl-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylic acid Ethyl ester;
[2R, 4S] 4-[(3,5-Bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -2-methyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1- Carboxylic acid ethyl ester;
[2R, 4S] 4-[(3,5-Bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -2-methyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1- Carboxylic acid isopropyl ester.

  Another class of CETP inhibitors that find utility in the present invention is the formula III

Consisting of ring-formed 4-carboxyamino-2-methyl-1,2,3,4-tetrahydroquinoline and their pharmaceutically acceptable forms having the formula:
[Wherein R _III-1 is hydrogen, Y _III , W _III -X _III , W _III -Y _III ;
Where W _III is carbonyl, thiocarbonyl, sulfinyl or sulfonyl;
X _III is, -OY _III, be _{-SY II, -N (H) -Y} III or -N- (Y _{III) 2;}
Y _III is independently for each occurrence Z _III or is a fully saturated, partially unsaturated or fully unsaturated 1-10 membered straight or branched carbon chain, where The carbons other than those bonded with may be optionally substituted with 1 or 2 heteroatoms independently selected from oxygen, sulfur and nitrogen, and the carbons may optionally be independently -, Di- or tri-substituted, the carbon is optionally mono-substituted by hydroxy, the carbon is optionally mono-substituted by oxo, the sulfur is optionally mono- or di-substituted by oxo, The nitrogen is optionally mono- or di-substituted by oxo and the carbon chain is optionally mono-substituted by Z _III ;
Where Z _III is a partially saturated, fully saturated or fully unsaturated 3-12 membered ring optionally having 1 to 4 heteroatoms independently selected from oxygen, sulfur and nitrogen. Two fused partially saturated, fully saturated or fully, optionally having 1 to 4 heteroatoms optionally selected independently from nitrogen, sulfur and oxygen A bicyclic ring consisting of an unsaturated 3- to 6-membered ring;
Wherein the Z _III substituent is optionally halogen, (C ₂ -C ₆ ) alkenyl, (C ₁ -C ₆ ) alkyl, hydroxy, (C ₁ -C ₆ ) alkoxy, (C ₁ -C ₄ ) alkylthio , Amino, nitro, cyano, oxo, carboxy, (C ₁ -C ₆ ) alkyloxycarbonyl, mono-N- or di-N, N- (C ₁ -C ₆ ) alkylamino independently mono-, di- -Or tri-substituted, wherein the (C ₁ -C ₆ ) alkyl substituent is optionally independently halogen, hydroxy, (C ₁ -C ₆ ) alkoxy, (C ₁ -C ₄ ) alkylthio, Amino, nitro, cyano, oxo, carboxyl, (C ₁ -C ₆ ) alkyloxycarbonyl, mono-N- or di-N, N- (C ₁ -C ₆ ) alkylamino mono-, di- or tri- Substituted, the (C ₁ -C ₆ ) alkyl is optionally substituted with 1 to 9 fluorines;
R _III-3 is hydrogen or Q _III ;
Where Q _III is a fully saturated, partially unsaturated or fully unsaturated 1-6 membered straight or branched carbon chain, where the carbons other than the carbons attached are: Optionally substituted with one heteroatom selected from oxygen, sulfur and nitrogen, and the carbon is optionally mono-, di- or tri-substituted independently by halogen, and the carbon is optionally hydroxy Optionally, the carbon is mono-substituted by oxo, the sulfur is optionally mono- or di-substituted by oxo, the nitrogen is optionally mono- or di-substituted by oxo, and The carbon chain is optionally mono-substituted by V _III ;
Where V _III is a partially saturated, fully saturated or fully unsaturated 3- to 12-membered ring optionally having 1 to 4 heteroatoms independently selected from oxygen, sulfur and nitrogen. Two fused partially saturated, fully saturated or fully unsaturated, optionally having 1 to 4 heteroatoms independently selected from nitrogen, sulfur and oxygen A bicyclic ring consisting of three to six members of
Wherein the V _III substituent is optionally halogen, (C ₁ -C ₆ ) alkyl, (C ₂ -C ₆ ) alkenyl, hydroxy, (C ₁ -C ₆ ) alkoxy, (C ₁ -C ₆ ) Alkylthio, amino, nitro, cyano, oxo, carboxamoyl, mono-N- or di-N, N- (C ₁ -C ₆ ) alkylcarboxamoyl, carboxy, (C ₁ -C ₆ ) alkyloxycarbonyl, mono- N- or di-N, N- (C ₁ -C ₆ ) alkylamino is independently mono-, di-, tri- or tetra-substituted where the (C ₁ -C ₆ ) alkyl or (C ₂ -C ₆ ) alkenyl substituents are optionally hydroxy, (C ₁ -C ₆ ) alkoxy, (C ₁ -C ₄ ) alkylthio, amino, nitro, cyano, oxo, carboxy, (C ₁ -C ₆ ) alkyl Mono-, di- or tri-substituted by oxycarbonyl, mono-N- or di-N, N- (C ₁ -C ₆ ) alkylamino, or the (C ₁ -C ₆ ) alkyl or ( C ₂ -C ₆₎ alkenyl Substituent is substituted by 1 to 9 fluorine optionally;
R _III-4 is Q _III or V _III-1 ;
Where Q _III-1 is a fully saturated, partially unsaturated or fully unsaturated 1-6 membered straight or branched carbon chain, where the carbon other than the carbon attached May be optionally substituted with one heteroatom selected from oxygen, sulfur and nitrogen, and the carbon is optionally mono-, di- or tri-substituted independently by halogen, the carbon being optional Optionally mono-substituted by hydroxy, the carbon is mono-substituted by oxo, the sulfur is optionally mono- or di-substituted by oxo, and the nitrogen is optionally mono- or di-substituted by oxo. And the carbon chain is optionally mono-substituted by V _III-1 ;
Where V _III-1 is a partially saturated, fully saturated or fully unsaturated 3-6 membered optionally having 1-2 heteroatoms independently selected from oxygen, sulfur and nitrogen. A ring of
Wherein the V _III-1 substituent is optionally halogen, (C ₁ -C ₆ ) alkyl, (C ₂ -C ₆ ) alkoxy, amino, nitro, cyano, (C ₁ -C ₆ ) alkyloxycarbonyl, Mono-N- or di-N, N- (C ₁ -C ₆ ) alkylamino independently mono-, di-, tri- or tetra-substituted, wherein said (C ₁ -C ₆ ) alkyl substitution The group is optionally mono-substituted by oxo and the (C ₁ -C ₆ ) alkyl substituent is optionally substituted by 1 to 9 fluorines;
Where either the R _III-3 substituent must contain V _III or R _III-4 must contain V _III-1 ; and
R _III-5 and R _III-6 , or R _III-6 and R _III-7 , and / or R _III-7 and R _III-8 are taken together and are optionally independent of nitrogen, sulfur and oxygen. Forming at least one 4- to 8-membered ring having 1 to 3 heteroatoms selected in the above, partially saturated or fully unsaturated;
Wherein the ring or the ring formed by R _III-5 and R _III-6 , or R _III-6 and R _III-7 , and / or R _III-7 and R _III-8 is optionally independently Halogen, (C ₁ -C ₆ ) alkyl, (C ₁ -C ₄ ) alkylsulfonyl, (C ₂ -C ₆ ) alkenyl, hydroxy, (C ₁ -C ₆ ) alkoxy, (C ₁ -C ₄ ) alkylthio, Amino, nitro, cyano, oxo, carboxy, (C ₁ -C ₆ ) alkyloxycarbonyl, mono-N- or di-N, N- (C ₁ -C ₆ ) alkylamino mono-, di- or tri- Substituted, wherein the (C ₁ -C ₆ ) alkyl substituent is hydroxy, (C ₁ -C ₆ ) alkoxy, (C ₁ -C ₄ ) alkylthio, amino, nitro, cyano, oxo, carboxy, (C _1- C ₆ ) alkyloxycarbonyl, mono-N- or di-N, N- (C ₁ -C ₆ ) alkylamino mono-, di- or tri-substituted, the (C ₁ -C ₆ ) Alkyl substituents are optionally substituted with 1 to 9 fluorines. Exchanged;
However, in some cases, R _III-5 , R _III-6 , R _III-7 and R _III-8 that do not form at least one ring are each independently hydrogen, halogen, (C ₁ -C ₆ ) alkoxy Or (C ₁ -C ₆ ) alkyl, the (C ₁ -C ₆ ) alkyl optionally having 1 to 9 fluorines. ].

  The compound of formula III is disclosed in US Pat. No. 6,147,089, assigned to the assignee of the present invention, the complete disclosure of which is hereby incorporated by reference.

In a preferred embodiment, the CETP inhibitor is selected from the following compounds of formula III:
[2R, 4S] 4-[(3,5-Bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -2-methyl-2,3,4,6,7,8-hexahydro-cyclopenta [g] Quinoline-1-carboxylic acid ethyl ester;
[6R, 8S] 8-[(3,5-Bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -6-methyl-3,6,7,8-tetrahydro-1H-2-thia-5- Aza-cyclopenta [b] naphthalene-5-carboxylic acid ethyl ester;
[6R, 8S] 8-[(3,5-Bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -6-methyl-3,6,7,8-tetrahydro-2H-furo [2,3- g] quinoline-5-carboxylic acid ethyl ester;
[2R, 4S] 4-[(3,5-Bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -2-methyl-3,4,6,8-tetrahydro-2H-furo [3,4- g] quinoline-1-carboxylic acid ethyl ester;
[2R, 4S] 4-[(3,5-Bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -2-methyl-3,4,6,7,8,9-hexahydro-2H-benzo [ g] quinoline-1-carboxylic acid propyl ester;
[7R, 9S] 9-[(3,5-Bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -7-methyl-1,2,3,7,8,9-hexahydro-6-aza- Cyclopenta [a] naphthalene-6-carboxylic acid ethyl ester; and
[6S, 8R] 6-[(3,5-Bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -8-methyl-1,2,3,6,7,8-hexahydro-9-aza- Cyclopenta [a] naphthalene-9-carboxylic acid ethyl ester.

  Another class of CETP inhibitors that find utility in the present invention is the formula IV

Consisting of 4-carboxyamino-2-substituted-1,2,3,4, -tetrahydroquinolines and their pharmaceutically acceptable forms:
[Wherein R _IV-1 is hydrogen, Y _IV , W _IV -X _IV , W _IV -Y _IV ;
Where W _IV is carbonyl, thiocarbonyl, sulfinyl or sulfonyl;
X _IV is -OY _IV , -SY _IV , -N (H) -Y _IV, or -N- (Y _IV ) ₂ ;
Y _IV is independently Z _IV for each occurrence, or is a fully saturated, partially unsaturated or fully unsaturated 1-10 member straight or branched carbon chain, where it is attached Carbons other than carbon may optionally be substituted with 1 or 2 heteroatoms independently selected from oxygen, sulfur and nitrogen, and the carbon may optionally be independently 1-, Di- or tri-substituted, the carbon is optionally mono-substituted by hydroxy, the carbon is optionally mono-substituted by oxo, the sulfur is optionally mono- or di-substituted by oxo and the nitrogen is Optionally mono- or di-substituted by oxo, and the carbon chain is optionally mono-substituted by Z _IV ;
Where Z _IV is a partially saturated, fully saturated or fully unsaturated 3-8 membered ring optionally having 1 to 4 heteroatoms independently selected from oxygen, sulfur and nitrogen. Two fused partially saturated, fully saturated or fully, optionally having 1 to 4 heteroatoms optionally selected independently from nitrogen, sulfur and oxygen A bicyclic ring consisting of an unsaturated 3- to 6-membered ring;
Wherein the Z _IV substituent is optionally halogen, (C ₂ -C ₆ ) alkenyl, (C ₁ -C ₆ ) alkyl, hydroxy, (C ₁ -C ₆ ) alkoxy, (C ₁ -C ₄ ) alkylthio , Amino, nitro, cyano, oxo, carboxy, (C ₁ -C ₆ ) alkyloxycarbonyl, mono-N- or di-N, N- (C ₁ -C ₆ ) alkylamino independently mono-, di- -Or tri-substituted, wherein the (C ₁ -C ₆ ) alkyl substituent is optionally independently halogen, hydroxy, (C ₁ -C ₆ ) alkoxy, (C ₁ -C ₄ ) alkylthio, Amino, nitro, cyano, oxo, carboxy, (C ₁ -C ₆ ) alkyloxycarbonyl, mono-N- or di-N, N- (C ₁ -C ₆ ) alkylamino mono-, di- or tri- Substituted and the (C ₁ -C ₆ ) alkyl substituent is also optionally substituted with 1 to 9 fluorines;
R _IV-2 is a 1- to 6-membered straight or branched carbon chain that is partially saturated, fully saturated, or fully unsaturated, where the carbon other than the bonded carbon is optionally oxygen. May be substituted with 1 or 2 heteroatoms independently selected from sulfur and nitrogen, and the carbon atoms are optionally mono-, di- or tri-substituted independently with halogen; Optionally mono-substituted by oxo, the carbon optionally mono-substituted by hydroxy, the sulfur optionally mono- or di-substituted by oxo, and the nitrogen optionally mono- or di-substituted by oxo Or the R _IV-2 optionally has 1-2 heteroatoms independently selected from oxygen, sulfur and nitrogen, partially saturated, fully saturated or fully unsaturated 3 to 7 membered ring, wherein the R _IV-2 ring is optionally linked via (C ₁ -C ₄ ) alkyl;
The R _IV-2 ring is optionally halogen, (C ₂ -C ₆ ) alkenyl, (C ₁ -C ₆ ) alkyl, hydroxy, (C ₁ -C ₆ ) alkoxy, (C ₁ -C ₄ ) alkylthio. Amino, nitro, cyano, oxo, carboxy, (C ₁ -C ₆ ) alkoxycarbonyl, mono-N- or di-N, N- (C ₁ -C ₆ ) alkylamino independently by mono-, di- , Or tri-substituted, wherein the (C ₁ -C ₆ ) alkyl substituent is optionally halogen, hydroxy, (C ₁ -C ₆ ) alkoxy, (C ₁ -C ₄ ) alkylthio, oxo or (C ₁ -C ₆ ) independently mono-, di- or tri-substituted by alkyloxycarbonyl;
Where R _IV-2 is not methyl;
R _IV-3 is hydrogen or Q _IV ;
Where Q _IV is a fully saturated, partially unsaturated or fully unsaturated 1 to 6 membered straight or branched carbon chain, where the carbons other than the attached carbon are Optionally substituted with one heteroatom selected from oxygen, sulfur and nitrogen, and the carbon is optionally mono-, di- or tri-substituted independently by halogen, and the carbon is optionally hydroxy The carbon is optionally mono-substituted by oxo, the sulfur is optionally mono- or di-substituted by oxo, the nitrogen is optionally mono- or di-substituted by oxo and the carbon The chain is optionally mono-substituted by V _IV ;
Where V _IV is a partially saturated, fully saturated or fully unsaturated 3-8 membered ring optionally having 1 to 4 heteroatoms independently selected from oxygen, sulfur and nitrogen. Two fused partially saturated, fully saturated or fully unsaturated, optionally having 1 to 4 heteroatoms independently selected from nitrogen, sulfur and oxygen A bicyclic ring consisting of three to six members of
Wherein the V _IV substituent is optionally halogen, (C ₁ -C ₆ ) alkyl, (C ₂ -C ₆ ) alkenyl, hydroxy, (C ₁ -C ₆ ) alkoxy, (C ₁ -C ₄ ) alkylthio , amino, nitro, cyano, oxo, Karubokisamoiru, mono- -N- or di _{-N, N- (C 1 -C 6} ) alkyl carboxamides moil, carboxy, (C ₁ -C ₆₎ alkyloxycarbonyl, mono -N -Or di-N, N- (C ₁ -C ₆ ) alkylamino independently mono-, di-, tri- or tetra-substituted, wherein said (C ₁ -C ₆ ) alkyl or (C ₂ -C ₆ ) alkenyl substituents are optionally independently hydroxy, (C ₁ -C ₆ ) alkoxy, (C ₁ -C ₄ ) alkylthio, amino, nitro, cyano, oxo, carboxy, (C ₁ -C ₆ ) Alkyloxycarbonyl, mono-N- or di-N, N- (C ₁ -C ₆ ) alkylamino mono-, di- or tri-substituted, said (C ₁ -C ₆ ) alkyl or (C ₂ -C ₆₎ alkenyl substituent, Ren It is optionally substituted with one to nine fluorine;
R _IV-4 is Q _IV or V _IV-1 ;
Where Q _IV-1 is a fully saturated, partially unsaturated or fully unsaturated 1-6 membered straight or branched carbon chain, with carbons other than the carbons attached here May be optionally substituted with one heteroatom selected from oxygen, sulfur and nitrogen, and the carbon is optionally mono-, di- or tri-substituted independently by halogen, the carbon being optional The carbon is optionally mono-substituted by oxo, the sulfur is optionally mono- or di-substituted by oxo and the nitrogen is optionally mono- or di-substituted by oxo. And the carbon chain is optionally mono-substituted by V _IV-1 ;
Where V _IV-1 is a partially saturated, fully saturated or fully unsaturated 3-6 membered optionally having 1-2 heteroatoms independently selected from oxygen, sulfur and nitrogen. A ring of
Wherein the V _IV-1 substituent is optionally halogen, (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkoxy, amino, nitro, cyano, (C ₁ -C ₆ ) alkyloxycarbonyl, Mono-N- or di-N, N- (C ₁ -C ₆ ) alkylamino independently mono-, di-, tri- or tetra-substituted, wherein said (C ₁ -C ₆ ) alkyl substitution The group is optionally mono-substituted by oxo and the (C ₁ -C ₆ ) alkyl substituent is optionally substituted by 1 to 9 fluorines;
Where either the R _IV-3 substituent must contain V _IV or R _IV-4 must contain V _IV-1 ; and
R _IV-5 , R _IV-6 , R _IV-7 and R _IV-8 are each independently hydrogen, a bond, nitro or halogen, wherein the bond is substituted by T _IV , or Substituted by a partially saturated, fully saturated or fully unsaturated (C ₁ -C ₁₂ ) linear or branched carbon chain, wherein the carbon is optionally independently selected from oxygen, sulfur and nitrogen Substituted with 1 or 2 heteroatoms, the carbon atom optionally mono-, di- or tri-substituted with halogen, the carbon optionally mono-substituted with hydroxy, and the carbon optionally with oxo one - substituted, said sulfur is optionally one by oxo - substituted one by nitrogen is optionally oxo - - or two or di - substituted, and the carbon one by arbitrarily T _IV - substituted;
Where T _IV is a partially saturated, fully saturated or fully unsaturated 3-8 membered ring optionally having 1 to 4 heteroatoms independently selected from oxygen, sulfur and nitrogen. Two fused partially saturated, fully saturated or fully, optionally having 1 to 4 heteroatoms optionally selected independently from nitrogen, sulfur and oxygen A bicyclic ring consisting of an unsaturated 3- to 6-membered ring;
Wherein the T _IV substituent is optionally independently halogen, (C ₁ -C ₆ ) alkyl, (C ₂ -C ₆ ) alkenyl, hydroxy, (C ₁ -C ₆ ) alkoxy, (C ₁ -C ₄ ) alkylthio, amino, nitro, cyano, oxo, carboxy, (C ₁ -C ₆ ) alkyloxycarbonyl, mono-N- or di-N, N- (C ₁ -C ₆ ) alkylamino mono-, di- -Or tri-substituted, wherein the (C ₁ -C ₆ ) alkyl substituent is optionally hydroxy, (C ₁ -C ₆ ) alkoxy, (C ₁ -C ₄ ) alkylthio, amino, nitro, cyano, Oxo, carboxy, (C ₁ -C ₆ ) alkyloxycarbonyl, mono-N- or di-N, N- (C ₁ -C ₆ ) alkylamino, independently mono-, di- or tri-substituted The (C ₁ -C ₆ ) alkyl substituent is also optionally substituted by 1 to 9 fluorines; and where R _IV-5 and R _IV-6 , or R _IV-6 and R _IV-7 And / or R _IV-7 and R _IV-8 together As well as at least one 4-8 membered ring, optionally saturated, or partially unsaturated, optionally having 1-3 heteroatoms independently selected from nitrogen, sulfur and oxygen. Can be formed;
Here, the ring or the ring formed by R _IV-5 and R _IV-6 , or R _IV-6 and R _IV-7 , and / or R _IV-7 and R _IV-8 is optionally independently Halogen, (C ₁ -C ₆ ) alkyl, (C ₁ -C ₄ ) alkylsulfonyl, (C ₂ -C ₆ ) alkenyl, hydroxy, (C ₁ -C ₆ ) alkoxy, (C ₁ -C ₄ ) alkylthio, Amino, nitro, cyano, oxo, carboxy, (C ₁ -C ₆ ) alkyloxycarbonyl, mono-N- or di-N, N- (C ₁ -C ₆ ) alkylamino mono-, di- or tri- Substituted, wherein the (C ₁ -C ₆ ) alkyl substituent is optionally independently hydroxy, (C ₁ -C ₆ ) alkoxy, (C ₁ -C ₄ ) alkylthio, amino, nitro, cyano, oxo , Carboxy, (C ₁ -C ₆ ) alkyloxycarbonyl, mono-N- or di-N, N- (C ₁ -C ₆ ) alkylamino, mono-, di- or tri-substituted and the (C ₁ -C ₆ ) alkyl substituents are optionally substituted by 1 to 9 fluorines. Provided that when R _IV-2 is carboxyl or (C ₁ -C ₄ ) alkylcarboxyl, R _IV-1 is not hydrogen. ].

  Compounds of formula IV are disclosed in US Pat. No. 6,197,786 assigned to the assignee of the present invention, the complete disclosure of which is hereby incorporated by reference.

In a preferred embodiment, the CETP inhibitor is selected from the following compounds of formula IV:
[2S, 4S] 4-[(3,5-Bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -2-isopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1- Carboxylic acid isopropyl ester;
[2S, 4S] 4-[(3,5-Bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -6-chloro-2-cyclopropyl-3,4-dihydro-2H-quinoline-1-carboxylic Acid isopropyl ester;
[2S, 4S] 2-Cyclopropyl-4-[(3,5-dichloro-benzyl) -methoxycarbonyl-amino] -6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylate ester;
[2S, 4S] 4-[(3,5-Bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -2-cyclopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1 -Carboxylic acid tert-butyl ester;
[2R, 4R] 4-[(3,5-Bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -2-cyclopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinaline-1 -Carboxylic acid isopropyl ester;
[2S, 4S] 4-[(3,5-Bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -2-cyclopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1 -Carboxylic acid isopropyl ester;
[2S, 4S] 4-[(3,5-Bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -2-cyclobutyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1- Carboxylic acid isopropyl ester;
[2R, 4S] 4-[(3,5-Bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1- Carboxylic acid isopropyl ester;
[2S, 4S] 4-[(3,5-Bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -2-methoxymethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1 -Carboxylic acid isopropyl ester;
[2R, 4S] 4-[(3,5-Bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1- Carboxylic acid 2-hydroxy-ethyl ester;
[2S, 4S] 4-[(3,5-Bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -2-cyclopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1 -Carboxylic acid ethyl ester;
[2R, 4S] 4-[(3,5-Bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1- Carboxylic acid ethyl ester;
[2S, 4S] 4-[(3,5-Bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -2-cyclopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1 -Carboxylic acid propyl ester; and
[2R, 4S] 4-[(3,5-Bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1- Carboxylic acid propyl ester.

  Another class of CETP inhibitors that have found utility in the present invention is the formula V

Consisting of 4-amino-substituted-2-substituted-1,2,3,4, -tetrahydroquinolines and their pharmaceutically acceptable forms:
[Wherein R _V-1 is Y _V , W _V -X _V , W _V -Y _V ;
Where W _V is carbonyl, thiocarbonyl, sulfinyl or sulfonyl;
X _V is -OY _V , -SY _V , -N (H) -Y _V or -N- (Y _V ) ₂ ;
Y _V is independently Z _V for each occurrence, or is a fully saturated, partially unsaturated or fully unsaturated 1-10 membered straight or branched carbon chain, where The carbons other than those bonded with may be optionally substituted with 1 or 2 heteroatoms independently selected from oxygen, sulfur and nitrogen, and the carbons may optionally be independently -, Di- or tri-substituted, wherein the carbon is optionally mono-substituted independently by hydroxy, the carbon is optionally mono-substituted by oxo and the sulfur is optionally mono- or di-substituted by oxo The nitrogen is optionally mono- or di-substituted by oxo, and the carbon chain is optionally mono-substituted by Z _V ;
Where Z _V is a partially saturated, fully saturated or fully unsaturated 3- to 8-membered ring optionally having 1 to 4 heteroatoms independently selected from oxygen, sulfur and nitrogen. Two fused partially saturated, fully saturated or fully, optionally having 1 to 4 heteroatoms optionally selected independently from nitrogen, sulfur and oxygen A bicyclic ring consisting of an unsaturated 3- to 6-membered ring;
Wherein the Z _V substituent is optionally halogen, (C ₂ -C ₆ ) alkenyl, (C ₁ -C ₆ ) alkyl, hydroxy, (C ₁ -C ₆ ) alkoxy, (C ₁ -C ₄ ) alkylthio , Amino, nitro, cyano, oxo, carboxy, (C ₁ -C ₆ ) alkyloxycarbonyl, mono-N- or di-N, N- (C ₁ -C ₆ ) alkylamino independently mono-, di- -Or tri-substituted, wherein the (C ₁ -C ₆ ) alkyl substituent is optionally independently halogen, hydroxy, (C ₁ -C ₆ ) alkoxy, (C ₁ -C ₄ ) alkylthio, Amino, nitro, cyano, oxo, carboxy, (C ₁ -C ₆ ) alkyloxycarbonyl, mono-N- or di-N, N- (C ₁ -C ₆ ) alkylamino mono-, di- or tri- Substituted and the (C ₁ -C ₆ ) alkyl substituent is also optionally substituted with 1 to 9 fluorines;
R _V-2 is a 1- to 6-membered straight or branched carbon chain that is partially saturated, fully saturated or fully unsaturated, where the carbon other than the bonded carbon is optionally oxygen May be substituted with 1 or 2 heteroatoms independently selected from sulfur and nitrogen, and the carbon atoms are optionally mono-, di- or tri-substituted independently with halogen; Optionally mono-substituted by oxo, the carbon optionally mono-substituted by hydroxy, the sulfur optionally mono- or di-substituted by oxo, and the nitrogen optionally mono- or di-substituted by oxo Or the R _V-2 optionally has 1-2 heteroatoms independently selected from oxygen, sulfur and nitrogen, partially saturated, fully saturated or fully unsaturated A 3- to 7-membered ring, wherein the R _V-2 ring is optionally linked via (C ₁ -C ₄ ) alkyl;
The R _V-2 ring is optionally halogen, (C ₂ -C ₆ ) alkenyl, (C ₁ -C ₆ ) alkyl, hydroxy, (C ₁ -C ₆ ) alkoxy, (C ₁ -C ₄ ) alkylthio. , Amino, nitro, cyano, oxo, carboxy, (C ₁ -C ₆ ) alkyloxycarbonyl, mono-N- or di-N, N- (C ₁ -C ₆ ) alkylamino independently mono-, di- -Or tri-substituted, wherein the (C ₁ -C ₆ ) alkyl substituent is optionally halogen, hydroxy, (C ₁ -C ₆ ) alkoxy, (C ₁ -C ₄ ) alkylthio, oxo or ( C ₁ -C ₆ ) alkyloxycarbonyl independently mono-, di- or tri-substituted;
R _V-3 is hydrogen or Q _V ;
Where Q _V is a fully saturated, partially unsaturated or fully unsaturated 1-6 membered straight or branched carbon chain, where carbons other than the carbons attached are: Optionally substituted with one heteroatom selected from oxygen, sulfur and nitrogen, and the carbon is optionally mono-, di- or tri-substituted independently by halogen, and the carbon is optionally hydroxy The carbon is optionally mono-substituted by oxo, the sulfur is optionally mono- or di-substituted by oxo, the nitrogen is optionally mono- or di-substituted by oxo and the carbon The chain is optionally mono-substituted by V _V ;
Where V _V is a partially saturated, fully saturated or fully unsaturated 3-8 membered ring optionally having 1 to 4 heteroatoms independently selected from oxygen, sulfur and nitrogen. Two fused partially saturated, fully saturated or fully unsaturated, optionally having 1 to 4 heteroatoms independently selected from nitrogen, sulfur and oxygen A bicyclic ring consisting of three to six members of
Wherein the V _V substituent is optionally halogen, (C ₁ -C ₆ ) alkyl, (C ₂ -C ₆ ) alkenyl, hydroxy, (C ₁ -C ₆ ) alkoxy, (C ₁ -C ₄ ) alkylthio , amino, nitro, cyano, oxo, Karubokisamoiru, mono- -N- or di _{-N, N- (C 1 -C 6} ) alkyl carboxamides moil, carboxy, (C ₁ -C ₆₎ alkyloxycarbonyl, mono -N -Or di-N, N- (C ₁ -C ₆ ) alkylamino independently mono-, di-, tri- or tetra-substituted, wherein said (C ₁ -C ₆ ) alkyl or (C ₂ -C ₆ ) alkenyl substituents are optionally independently hydroxy, (C ₁ -C ₆ ) alkoxy, (C ₁ -C ₄ ) alkylthio, amino, nitro, cyano, oxo, carboxy, (C ₁ -C ₆ ) Alkyloxycarbonyl, mono-N- or di-N, N- (C ₁ -C ₆ ) alkylamino mono-, di- or tri-substituted, said (C ₁ -C ₆ ) alkyl or (C ₂ -C ₆₎ 1 to 9 alkenyl, optionally Of which is substituted by fluorine;
R _V-4 is cyano, formyl, W _V-1 Q _V-1 , W _V-1 V _V-1 , (C ₁ -C ₄ ) alkylene V _V-1 or V _V-2 ;
Where W _V-1 is carbonyl, thiocarbonyl, SO or SO ₂ ,
Where Q _V-1 is a fully saturated, partially unsaturated or fully unsaturated 1-6 membered straight or branched carbon chain, where carbon is optionally oxygen, sulfur And optionally substituted with one heteroatom selected from nitrogen and the carbon is optionally mono-, di- or tri-substituted independently by halogen, the carbon optionally mono-substituted by hydroxy The carbon is optionally mono-substituted by oxo, the sulfur is optionally mono- or di-substituted by oxo, the nitrogen is optionally mono- or di-substituted by oxo, and the carbon chain is optionally Is mono-substituted by V _V-1 ;
Where V _V-1 is a partially saturated, fully saturated or fully unsaturated 3-6 membered optionally having 1-2 heteroatoms independently selected from oxygen, sulfur and nitrogen. Two fused partially saturated, fully saturated, optionally having 1 to 4 heteroatoms independently selected from nitrogen, sulfur and oxygen Or a bicyclic ring consisting of a fully unsaturated 3-6 membered ring;
Wherein the V _V-1 substituent is halogen, (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkoxy, hydroxy, oxo, amino, nitro, cyano, (C ₁ -C ₆ ) alkyloxy Mono-, di-, tri- or tetra-substituted by carbonyl, mono-N- or di-N, N- (C ₁ -C ₆ ) alkylamino, wherein the (C ₁ -C ₆ ) alkyl substituent Is optionally mono-substituted by oxo and the (C ₁ -C ₆ ) alkyl substituent is also optionally substituted by 1 to 9 fluorines;
Where V _V-2 is a partially saturated, fully saturated or fully unsaturated 5-7 member optionally containing 1-4 heteroatoms independently selected from oxygen, sulfur and nitrogen. A ring of
Wherein the V _V-2 substituent is optionally mono-, di- or tri-, independently by halogen, (C ₁ -C ₂ ) alkyl, (C ₁ -C ₂ ) alkoxy, hydroxy, or oxo. Substituted, wherein the (C ₁ -C ₂ ) alkyl optionally has 1 to 5 fluorines;
Where R _V-4 does not include oxycarbonyl directly linked to the C ₄ nitrogen;
Where R _V-3 must contain V _V or R _V-4 must contain V _V-1 ; and
R _V-5 , R _V-6 , R _V-7 and R _V-8 are each independently hydrogen, a bond, nitro or halogen, wherein the bond is substituted by T _V , or Substituted by a partially saturated, fully saturated or fully unsaturated (C ₁ -C ₁₂ ) linear or branched carbon chain, wherein the carbon is optionally independently selected from oxygen, sulfur and nitrogen Substituted with 1 or 2 heteroatoms, the carbon is optionally mono-, di- or tri-substituted with halogen, the carbon is optionally mono-substituted with hydroxy, and the carbon is optionally mono-substituted with oxo. -Substituted, the sulfur is optionally mono- or di-substituted by oxo, the nitrogen is optionally mono- or di-substituted by oxo, and the carbon is optionally mono-substituted by T _V ;
Where T _V has 1 to 4 heteroatoms optionally selected independently from nitrogen, sulfur and oxygen, and is a partially saturated, fully saturated or fully unsaturated 3-12 membered. Two fused partially saturated, fully saturated or fully ring, or independently viewed, optionally having 1 to 4 heteroatoms selected from nitrogen, sulfur and oxygen A bicyclic ring consisting of a fully unsaturated 3-6 membered ring;
Wherein the T _V substituent is optionally independently halogen, (C ₁ -C ₆ ) alkyl, (C ₂ -C ₆ ) alkenyl, hydroxy, (C ₁ -C ₆ ) alkoxy, (C ₁ -C ₄ ) alkylthio, amino, nitro, cyano, oxo, carboxy, (C ₁ -C ₆ ) alkyloxycarbonyl, mono-N- or di-N, N- (C ₁ -C ₆ ) alkylamino mono-, di- -Or tri-substituted, wherein the (C ₁ -C ₆ ) alkyl substituent is optionally hydroxy, (C ₁ -C ₆ ) alkoxy, (C ₁ -C ₄ ) alkylthio, amino, nitro, cyano, Oxo, carboxy, (C ₁ -C ₆ ) alkyloxycarbonyl, mono-N- or di-N, N- (C ₁ -C ₆ ) alkylamino, independently mono-, di- or tri-substituted The (C ₁ -C ₆ ) alkyl substituent is also optionally substituted by 1 to 9 fluorines;
Where R _V-5 and R _V-6 , or R _V-6 and R _V-7 , and / or R _V-7 and R _V-8 may be together and from nitrogen, sulfur and oxygen Can form at least one partially saturated or fully unsaturated 4-8 membered ring, optionally having 1 to 3 heteroatoms independently selected;
Wherein the ring formed by R _V-5 and R _V-6 , or R _V-6 and R _V-7 , and / or R _V-7 and R _V-8 is optionally independently halogen, (C ₁ -C ₆ ) alkyl, (C ₁ -C ₄ ) alkylsulfonyl, (C ₂ -C ₆ ) alkenyl, hydroxy, (C ₁ -C ₆ ) alkoxy, (C ₁ -C ₄ ) alkylthio, amino, Nitro, cyano, oxo, carboxy, (C ₁ -C ₆ ) alkyloxycarbonyl, mono-N- or di-N, N- (C ₁ -C ₆ ) alkylamino mono-, di- or tri-substituted Where the (C ₁ -C ₆ ) alkyl substituent is optionally independently hydroxy, (C ₁ -C ₆ ) alkoxy, (C ₁ -C ₄ ) alkylthio, amino, nitro, cyano, oxo, carboxy , (C ₁ -C ₆ ) alkyloxycarbonyl, mono-N- or di-N, N- (C ₁ -C ₆ ) alkylamino, mono-, di- or tri-substituted, the (C ₁ -C ₆ ) The alkyl substituent is also optionally substituted by 1 to 9 fluorines. ].

  Compounds of formula V are disclosed in US Pat. No. 6,140,343, assigned to the assignee of the present invention, the complete disclosure of which is hereby incorporated by reference.

In a preferred embodiment, the CETP inhibitor is selected from the following compounds of formula V:
[2S, 4S] 4-[(3,5-Bis-trifluoromethyl-benzyl) -formyl-amino] -2-cyclopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1- Carboxylic acid isopropyl ester;
[2S, 4S] 4-[(3,5-Bis-trifluoromethyl-benzyl) -formyl-amino] -2-cyclopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1- Carboxylic acid propyl ester;
[2S, 4S] 4- [Acetyl- (3,5-bis-trifluoromethyl-benzyl) -amino] -2-cyclopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1- Carboxylic acid tert-butyl ester;
[2R, 4S] 4- [Acetyl- (3,5-bis-trifluoromethyl-benzyl) -amino] -2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxyl Acid isopropyl ester;
[2R, 4S] 4- [Acetyl- (3,5-bis-trifluoromethyl-benzyl) -amino] -2-methyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic Acid ethyl ester;
[2S, 4S] 4- [1- (3,5-Bis-trifluoromethyl-benzyl) -ureido] -2-cyclopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1- Carboxylic acid isopropyl ester;
[2R, 4S] 4- [Acetyl- (3,5-bis-trifluoromethyl-benzyl) -amino] -2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxyl Acid ethyl ester;
[2S, 4S] 4- [Acetyl- (3,5-bis-trifluoromethyl-benzyl) -amino] -2-methoxymethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1- Carboxylic acid isopropyl ester;
[2S, 4S] 4- [Acetyl- (3,5-bis-trifluoromethyl-benzyl) -amino] -2-cyclopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1- Carboxylic acid propyl ester;
[2S, 4S] 4- [Acetyl- (3,5-bis-trifluoromethyl-benzyl) -amino] -2-cyclopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1- Carboxylic acid ethyl ester;
[2R, 4S] 4-[(3,5-Bis-trifluoromethyl-benzyl) -formyl-amino] -2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic Acid isopropyl ester;
[2R, 4S] 4-[(3,5-Bis-trifluoromethyl-benzyl) -formyl-amino] -2-methyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxyl Acid ethyl ester;
[2S, 4S] 4- [Acetyl- (3,5-bis-trifluoromethyl-benzyl) -amino] -2-cyclopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1- Carboxylic acid isopropyl ester;
[2R, 4S] 4-[(3,5-Bis-trifluoromethyl-benzyl) -formyl-amino] -2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic Acid ethyl ester;
[2S, 4S] 4-[(3,5-Bis-trifluoromethyl-benzyl) -formyl-amino] -2-cyclopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1- Carboxylic acid ethyl ester;
[2R, 4S] 4-[(3,5-Bis-trifluoromethyl-benzyl) -formyl-amino] -2-methyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxyl Acid isopropyl ester; and
[2R, 4S] 4- [Acetyl- (3,5-bis-trifluoromethyl-benzyl) -amino] -2-methyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic Acid isopropyl ester.

  Another class of CETP inhibitors that have found utility in the present invention is the formula VI

Consisting of cycloalkano-pyridines and their pharmaceutically acceptable forms having:
Wherein A _VI is a straight or branched chain containing up to 5 identical or different substituents in the form of halogen, nitro, hydroxyl, trifluoromethyl, trifluoromethoxy, or up to 7 carbon atoms An aryl containing 6 to 10 carbon atoms, optionally substituted with an alkyl, acyl, hydroxyalkyl or alkoxy, or each or a group form according to the formula -NR _VI-3 R _VI-4 ,
Where R _VI-3 and R _VI-4 are the same or different and mean hydrogen, phenyl or straight-chain or branched alkyl containing up to 6 carbon atoms,
D _VI is aryl containing 6 to 10 carbon atoms optionally substituted by phenyl, nitro, halogen, trifluoromethyl or trifluoromethoxy, or the formula R _VI-5 -L _VI- ,

Or the formula R _VI-9 -T _VI -V _VI -X _VI
Wherein R _VI-5 , R _VI-6 and R _VI-9 are, independently of one another, cycloalkyl containing 3 to 6 carbon atoms, or aryl containing 6 to 10 carbon atoms, or S, 5- to 7-membered, optionally benzo-fused, saturated or unsaturated, mono-, bi- or tricyclic containing up to 4 heteroatoms from the N and / or O pair Means a heterocycle, where these rings are N-functional nitrogen-containing rings, halogen, trifluoromethyl, nitro, hydroxyl, cyano, carboxyl, trifluoromethoxy, each up to 6 carbon atoms Linear or branched acyl, alkyl, alkylthio, alkylalkoxy, alkoxy or alkoxycarbonyl, aryl containing 6 to 10 carbon atoms each or trifluoromethyl-substituted aryl, or optionally benzo- Condensed, S, N And / or optionally substituted with up to 5 identical or different substituents in the form of an aromatic 5- to 7-membered heterocycle containing up to 3 heteroatoms in the set of O and / or -OR _VI-10 , -SR _VI-11 , -SO ₂ R _VI-12 or -NR _VI-13 R _VI-14
R _VI-10 , R _VI-11 and R _VI-12 here, independently of one another, mean aryl containing 6 to 10 carbon atoms, which in turn is phenyl, halogen or up to 6 Substituted with up to two identical or different substituents in the form of straight-chain or branched alkyl containing carbon atoms,
R _VI-13 and R _VI-14 are the same or different and have the meaning of R _VI-3 and R _{VI-4 set} forth above, or
R _VI-5 and / or R _VI-6 is

Means the radical of
R _VI-7 means hydrogen or halogen, and
R _VI-8 is hydrogen, halogen, azide, trifluoromethyl, hydroxyl, trifluoromethoxy, straight or branched alkoxy or alkyl each containing up to 6 carbon atoms, or the following formula:

Means the radical of
(Wherein R _VI-15 and R _VI-16 are the same or different and have the meanings of R _VI-3 and R _VI-4 shown above), or
R _VI-7 and R _VI-8 together form a radical of formula = O or = NR _VI-17 ,
Where R _VI-17 means hydrogen or straight-chain or branched alkyl, alkoxy or acyl each containing up to 6 carbon atoms,
L _VI means a straight or branched alkylene or alkenylene chain, each containing up to 8 carbon atoms, optionally substituted by up to 2 hydroxyl groups;
T _VI and X _VI mean the same or different and straight or branched alkylene chains containing up to 8 carbon atoms,
T _VI and X _VI mean a bond,
V _VI means an oxygen or sulfur atom, or a —NR _VI-18 group,
R _VI-18 here represents hydrogen or straight-chain or branched alkyl or phenyl containing up to 6 carbon atoms,
E _VI is a cycloalkyl containing 3 to 8 carbon atoms, or a linear or branched alkyl containing up to 8 carbon atoms, optionally substituted with 3 to 8 carbon atoms or hydroxyl, Means cycloalkyl, or phenyl optionally substituted by halogen or trifluoromethyl;
R _VI-1 and R _VI-2 together form a linear or branched alkylene chain containing up to 7 carbon atoms, which is a carbonyl group and / or

Must be replaced by the radical of
Where a and b are the same or different and mean a number equal to 1, 2 or 3,
R _VI-19 is a hydrogen atom, a cycloalkyl containing 3 to 7 carbon atoms, a straight chain or branched silylalkyl containing up to 8 carbon atoms, or a straight chain containing up to 8 carbon atoms. Or branched alkyl, which is optionally substituted by hydroxyl, straight or branched alkoxy containing up to 6 carbon atoms, or phenyl, which is then halogen, nitro, trifluoromethyl Substituted with alkyl, optionally substituted with a group of formula -OR _VI-22 , and trifluoromethoxy or phenyl or tetrazole-substituted phenyl
Where R _VI-22 means a straight or branched acyl containing up to 4 carbon atoms or benzyl, or
R _VI-19 is a linear or branched acyl containing up to 20 carbon atoms, or benzoyl optionally substituted with halogen, trifluoromethyl, nitro or trifluoromethoxy, or up to 8 carbon atoms Means a linear or branched fluoroacyl containing
R _VI-20 and R _VI-21 are the same or different and represent hydrogen, phenyl, or straight-chain or branched-alkyl containing up to 6 carbon atoms, or
R _VI-20 and R _VI-21 together form a 3- to 6-membered carbocyclic ring, and the formed carbocyclic rings are optionally also geminal, 3 to 7 each. Up to 6 identical or different substituents in the form of trifluoromethyl, hydroxyl, nitrile, halogen, carboxyl, nitro, azide, cyano, cycloalkyl or cycloalkyloxy, each containing up to 6 carbon atoms Optionally substituted by linear or branched alkoxycarbonyl, alkoxy or alkylthio, or linear or branched alkyl containing up to 6 carbon atoms, which in turn is hydroxyl, benzyloxy , Trifluoromethyl, benzoyl in the form of up to 2 identical or different substituents, each linear or branched alkoxy, oxyacyl or cation containing up to 4 carbon atoms The carbocyclic ring which is substituted by ruboxyl and / or phenyl, which is then substituted by halogen, trifluoromethyl or trifluoromethoxy, and / or is optionally also geminal, phenyl, benzoyl, thiophenyl Or optionally substituted by up to 5 same or different substituents in the form of sulfonylbenzyl, which is then halogen, trifluoromethyl, trifluoromethoxy or nitro, and / or optionally

Optionally substituted by the radical form of:
[Wherein c is a number equal to 1, 2, 3 or 4;
d is a number equal to 0 or 1,
R _VI-23 and R _VI-24 are the same or different and are hydrogen, cycloalkyl containing 3 to 6 carbon atoms, linear or branched alkyl containing up to 6 carbon atoms, benzyl or phenyl Which is optionally substituted by up to two identical or different substituents in the form of halogen, trifluoromethyl, cyano, phenyl or nitro, and / or the carbocyclic ring formed is of the formula

Optionally substituted by a spiro-linked radical of:
Here, W _VI means either an oxygen atom or a sulfur atom,
Y _VI and Y ′ _VI together form a 2- to 6-membered linear or branched alkylene chain,
e is a number equal to 1, 2, 3, 4, 5, 6 or 7,
f is a number equal to 1 or 2,
R _VI-25 , R _VI-26 , R _VI-27 , R _VI-28 , R _VI-29 , R _VI-30 and R _VI-31 are the same or different, and hydrogen, trifluoromethyl, phenyl, halogen Or straight or branched alkyl or alkoxy each containing up to 6 carbon atoms, or
R _VI-25 and R _VI-26 or R _VI-27 and R _VI-28 together with each other means a straight or branched alkyl chain containing up to 6 carbon atoms, or
R _VI-25 and R _VI-26 or R _VI-27 and R _VI-28 are

Forms radicals of:
Where W _VI has the meaning indicated above,
g is a number equal to 1, 2, 3, 4, 5, 6 or 7,
R _VI-32 and R _VI-33 together form a 3- to 7-membered heterocycle, which contains an oxygen or sulfur atom, or a group of formula SO, SO ₂ or —NR _VI-34 ,
R _VI-34 means a hydrogen atom, phenyl, benzyl, or straight-chain or branched alkyl containing up to 4 carbon atoms. ), And their salts and N oxides,
However, 5 (6H) -quinolone and 3-benzoyl-7,8-dihydro-2,7,7-trimethyl-4-phenyl are excluded. ].

  Compounds of formula VI are disclosed in European patent application EP 818448 A1, the full disclosure of which is hereby incorporated by reference.

In a preferred embodiment, the CETP inhibitor is selected from the following compounds of formula VI:
2-cyclopentyl-4- (4-fluorophenyl) -7,7-dimethyl-3- (4-trifluoromethylbenzoyl) -4,6,7,8-tetrahydro-1H-quinolin-5-one;
2-cyclopentyl-4- (4-fluorophenyl) -7,7-dimethyl-3- (4-trifluoromethylbenzoyl) -7,8-dihydro-6H-quinolin-5-one;
[2-Cyclopentyl-4- (4-fluorophenyl) -5-hydroxy-7,7-dimethyl-5,6,7,8-tetrahydroquinolin-3-yl]-(4-trifluoromethylphenyl) -methanone ;
[5- (t-butyldimethylsilanyloxy) -2-cyclopentyl-4- (4-fluorophenyl) -7,7-dimethyl-5,6,7,8-tetrahydroquinolin-3-yl]-(4 -Trifluoromethylphenyl) -methanone;
[5- (t-butyldimethylsilanyloxy) -2-cyclopentyl-4- (4-fluorophenyl) -7,7-dimethyl-5,6,7,8-tetrahydroquinolin-3-yl]-(4 -Trifluoromethylphenyl) -methanol;
5- (t-butyldimethylsilanyloxy) -2-cyclopentyl-4- (4-fluorophenyl) -3- [fluoro- (4-trifluoromethylphenyl) -methyl] -7,7-dimethyl-5, 6,7,8-tetrahydroquinoline;
2-Cyclopentyl-4- (4-fluorophenyl) -3- [fluoro- (4-trifluoromethylphenyl) -methyl] -7,7-dimethyl-5,6,7,8-tetrahydroquinolin-5-ol .

  Another class of CETP inhibitors that have found utility in the present invention is the formula VII

Consisting of substituted -pyridines and their pharmaceutically acceptable forms having:
Wherein R _VII-2 and R _VII-6 are hydrogen, hydroxy, alkyl, fluorinated alkyl, fluorinated aralkyl, chlorofluorinated alkyl, cycloalkyl, heterocyclic aryl, heteroaryl Independently selected from the group consisting of, alkoxy, alkoxyalkyl, and alkoxycarbonyl; provided that at least one of R _VII-2 and R _VII-6 is fluorinated alkyl, chlorofluorinated alkyl or alkoxyalkyl Is;
R _VII-3 is selected from the group consisting of hydroxy, amide, arylcarbonyl, heteroarylcarbonyl, hydroxymethyl-CHO, —CO ₂ R _VII-7 , wherein R _VII-7 is hydrogen, alkyl and cyanoalkyl ;as well as

Wherein R _VII-15a is hydroxy, hydrogen, halogen, alkylthio, alkenylthio, alkynylthio, arylthio, heteroarylthio, heterocyclic thio, alkoxy, alkeneoxy, alkyneoxy, aryloxy, heteroaryloxy and Selected from the group consisting of heterocyclic oxy, and
R _VII-16a is selected from the group consisting of alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, and heterocycle, arylalkoxy, trialkylsilyloxy. ) Selected from the group consisting of;
R _VII-4 is hydrogen, hydroxy, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, haloalkyl, haloalkenyl, haloalkynyl, aryl, heteroaryl, heterocycle, cycloalkylalkyl, cycloalkenylalkyl, aralkyl, Heteroarylalkyl, heterocyclic alkyl, cycloalkylalkenyl, cycloalkenylalkenyl, aralkenyl, heteroarylalkenyl, heterocyclicalkenyl, alkoxy, alkeneoxy, alkyneoxy, aryloxy, heteroaryloxy, heterocyclicoxy, alkanoyloxy , Alkenoyloxy, alkinoyloxy, aryloyloxy, heteroaroyloxy, heterocyclic yloxy, alkoxycarbonyl, alkeneoxy Sicarbonyl, alkyneoxycarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl, heterocyclic oxycarbonyl, thio, alkylthio, alkenylthio, alkynylthio, arylthio, heteroarylthio, heterocyclic thio, cycloalkylthio, cycloalkenylthio, Alkylthioalkyl, alkenylthioalkyl, alkynylthioalkyl, arylthioalkyl, heteroarylthioalkyl, heterocyclic thioalkyl, alkylthioalkenyl, alkenylthioalkenyl, alkynylthioalkenyl, arylthioalkenyl, heteroarylthioalkenyl, heterocyclic thioalkenyl Alkylamino, alkenylamino, alkynylamino, arylamino, heteroarylamino, hetero Wherein amino, aryl dialkylamino, diarylamino, diheteroarylamino, alkylarylamino, alkylheteroaryl amino, aryl heteroaryl amino, trialkylsilyl, tri alkenyl silyl, triarylsilyl, -CO (O) N (R VII _-8a R _VII-8b ), wherein R _VII-8a and R _VII-8b are independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heteroaryl and heterocyclic. SO ₂ R _VII-9 (wherein R _VII-9 is selected from the group consisting of hydroxy, alkyl, alkenyl, alkynyl, aryl, heteroaryl and heterocyclic), —OP (O) (OR _{VII -10a} ) (OR _VII-10b ) wherein R _VII-10a and R _VII-10b are independently composed of hydrogen, hydroxy, alkyl, alkenyl, alkynyl, aryl, heteroaryl and heterocyclic. Selected from the group. ), And -OP (S) (OR _VII-11a ) (OR _VII-11b ) (wherein R _VII-11a ) and R _VII-11b are independently alkyl, alkenyl, alkynyl, aryl, heteroaryl and Selected from the group consisting of heterocyclyl. ) Selected from the group consisting of:
R _VII-5 is hydrogen, hydroxy, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, haloalkyl, haloalkenyl, haloalkynyl, aryl, heteroaryl, heterocycle, alkoxy, alkeneoxy, alkyneoxy, aryloxy , Heteroaryloxy, heterocyclic oxy, alkylcarbonyloxyalkyl, alkenylcarbonyloxyalkyl, alkynylcarbonyloxyalkyl, arylcarbonyloxyalkyl, heteroarylcarbonyloxyalkyl, heterocyclic carbonyloxyalkyl, cycloalkylalkyl, cycloalkenylalkyl , Aralkyl, heteroarylalkyl, heterocyclic alkyl, cycloalkylalkenyl, cycloalkenylalkenyl, ara Lucenyl, heteroarylalkenyl, heterocyclicalkenyl, alkylthioalkyl, cycloalkylthioalkyl, alkenylthioalkyl, alkynylthioalkyl, arylthioalkyl, heteroarylthioalkyl, heterocyclic thioalkyl, alkylthioalkenyl, alkenylthioalkenyl, alkynylthioalkenyl , Arylthioalkenyl, heteroarylthioalkenyl, heterocyclic thioalkenyl, alkoxyalkyl, alkeneoxyalkyl, alkyneoxylalkyl, aryloxyalkyl, heteroaryloxyalkyl, heterocyclicoxyalkyl, alkoxyalkenyl, alkeneoxyalkenyl, alkyne Oxyalkenyl, aryloxyalkenyl, heteroaryloxyalkenyl Heterocyclic oxy, cycloalkenyl, cyano, hydroxymethyl, -CO ₂ R _VII-14 (wherein, R _VII-14 is alkyl, alkenyl, alkynyl, aryl, selected from the group consisting of heteroaryl and heterocyclic. );

Wherein R _VII-15b is hydroxy, hydrogen, halogen, alkylthio, alkenylthio, alkynylthio, arylthio, heteroarylthio, heterocyclic thio, alkoxy, alkeneoxy, alkyneoxy, aryloxy, heteroaryloxy, Selected from the group consisting of heterocyclic oxy, aroyloxy, and alkylsulfonyloxy, and
R _VII-16b is selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycle, arylalkoxy, and trialkylsilyloxy. );

Wherein R _VII-17 and R _VII-18 are independently selected from the group consisting of alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl and heterocyclic.

Wherein R _VII-19 is alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycle, -SR _VII-20 , -OR _VII-21 , and -R _VII-22 CO ₂ R _VII- Selected from the group consisting of ₂₃ ,
Where R _VII-20 is alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycle, aminoalkyl, aminoalkenyl, aminoalkynyl, aminoaryl, aminoheteroaryl, aminoheterocycle, alkylheteroarylamino, arylheteroaryl Selected from the group consisting of amino;
R _VII-21 is selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heteroaryl and heterocyclic;
R _VII-22 is selected from the group consisting of alkylene or arylene;
R _VII-23 is selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heteroaryl, and heterocyclic. );

Wherein R _VII-24 is selected from the group consisting of hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycle, aralkyl, aralkenyl, and aralkynyl);

(Wherein R _VII-25 is heterocyclidenyl);

Wherein R _VII-26 and R _VII-27 are independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, and heterocyclic.

Wherein R _VII-28 and R _VII-29 are independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, and heterocyclic.

Wherein R _VII-30 and R _VII-31 are independently alkoxy, alkeneoxy, alkyneoxy, aryloxy, heteroaryloxy, and heterocyclic oxy;

Wherein R _VII-32 and R _VII-33 are independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, and heterocyclyl.

Wherein R _VII-36 is selected from the group consisting of alkyl, alkenyl, aryl, heteroaryl and heterocyclic.

Wherein R _VII-37 and R _VII-38 are independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, and heterocyclic.

Wherein R _VII-39 is hydrogen, alkoxy, alkeneoxy, alkyneoxy, aryloxy, heteroaryloxy, heterocyclicoxy, alkylthio, alkenylthio, alkynylthio, arylthio, heteroarylthio and heterocyclic thio Selected from the group consisting of, and
R _VII-40 is haloalkyl, haloalkenyl, haloalkynyl, haloaryl, haloheteroaryl, haloheterocycle, cycloalkyl, cycloalkenyl, heterocyclicalkoxy, heterocyclicalkeneoxy, heterocyclicalkyneoxy, alkylthio, alkenylthio , Alkynylthio, arylthio, heteroarylthio and heterocyclic thio. );

Wherein R _VII-41 is heterocyclidenyl.

Wherein R _VII-42 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, and heterocyclic, and
R _VII-43 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycle, cycloalkyl, cycloalkenyl, haloalkyl, haloalkenyl, haloalkynyl, haloaryl, haloheteroaryl, and haloheterocyclic Selected. );

Wherein R _VII-44 is selected from the group consisting of hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl and heterocyclic.

Wherein R _VII-45 is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycle, haloalkyl, haloalkenyl, haloalkynyl, haloaryl, haloheteroaryl, haloheterocycle, heterocycle, cycloalkylalkyl, Cycloalkenylalkyl, aralkyl, heteroarylalkyl, heterocyclic alkyl, cycloalkylalkenyl, cycloalkenylalkenyl, aralkenyl, heteroarylalkenyl, heterocyclicalkenyl, alkylthioalkyl, alkenylthioalkyl, alkynylthioalkyl, arylthioalkyl, hetero Arylthioalkyl, heterocyclic thioalkyl, alkylthioalkenyl, alkenylthioalkenyl, alkynylthioalkenyl, arylthioalkenyl, hete Arylthio alkenyl, heterocyclic thioalkenyl, aminocarbonyl alkyl, aminocarbonyl, cycloalkenyl, aminocarbonyl alkynyl, aminocarbonyl aryl, aminocarbonyl heteroaryl, and is selected from the group consisting of aminocarbonyl heterocyclic).;

Wherein SR _VII-46 is selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heteroaryl and heterocyclic, and
R _VII-47 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl and heterocyclic. ); And

Wherein R _VII-48 is selected from the group consisting of hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl and heterocyclic, and
R _VII-49 is selected from the group consisting of alkoxy, alkeneoxy, alkyneoxy, aryloxy, heteroaryloxy, heterocyclicoxy, haloalkyl, haloalkenyl, haloalkynyl, haloaryl, haloheteroaryl and haloheterocyclic . );

Wherein R _VII-50 consists of hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycle, alkoxy, alkeneoxy, alkyneoxy, aryloxy, heteroaryloxy and heterocyclicoxy Selected from the group);

Wherein R _VII-51 is selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycle, haloalkyl, haloalkenyl, haloalkynyl, haloaryl, haloheteroaryl and haloheterocyclic. And

Wherein R _VII-53 is selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heteroaryl and heterocyclyl;
Wherein R _VII-5 is selected from the group consisting of heterocyclic alkyl and heterocyclic alkenyl, and the corresponding heterocyclic alkyl or heterocyclic radical of heterocyclic alkenyl is other than δ-lactone; and Provided that R _VII-4 is aryl, heteroaryl or heterocyclic, and one of R _VII-2 and R _VII-6 is trifluoromethyl, and the other of R _VII-2 and R _VII-6 is Difluoromethyl. )].

  The compound of formula VII is disclosed in WO 9941237-A1, the full disclosure of which is incorporated herein by reference.

In a preferred embodiment, the CETP inhibitor is selected from compounds of formula VII:
Dimethyl 5,5'-dithiobis [2-difluoromethyl-4- (2-methylpropyl) -6- (trifluoromethyl) -3-pyridine-carboxylate].

  Another class of CETP inhibitors that have found utility in the present invention is the formula VIII:

Consisting of substituted pyridines and biphenyls and their pharmaceutically acceptable forms having:
Wherein A _VIII means aryl with 6-10 carbon atoms, which is up to 3 times in the same manner or differently, by halogen, hydroxy, trifluoromethyl, trifluoromethoxy, or By straight-chain or branched alkyl, acyl, or alkoxy with up to 7 carbon atoms or by the formula

Base of
(Wherein R _VIII-1 and R _VIII-2 are the same or different and mean hydrogen, phenyl, or straight or branched alkyl with up to 6 carbon atoms.)
Is optionally replaced by
D _VIII means a straight or branched alkyl with up to 8 carbon atoms, substituted by hydroxy,
E _VIII and L _VIII are either the same or different and are linear or branched with up to 8 carbon atoms, optionally substituted by cycloalkyl with 3 to 8 carbon atoms. Means alkyl or cycloalkyl with 3 to 8 carbon atoms, or
E _VIII has the aforementioned meaning, and
L _VIII is in this case up to 3 times, in the same manner or differently, by halogen, hydroxy, trifluoromethyl, trifluoromethoxy or linear or branched alkyl with up to 7 carbon atoms each By acyl, alkoxy, or

Base of
(Wherein R _VIII-3 and R _VIII-4 are the same or different and have the meanings previously defined for R _VIII-1 and R _VIII-2 ).
Means optionally substituted aryl with 6 to 10 carbon atoms, or
E _VIII means straight-chain or branched alkyl with up to 8 carbon atoms or aryl with 6-10 carbon atoms, which is up to 3 times in the same manner Or, as different, by halogen, hydroxy, trifluoromethyl, trifluoromethoxy, or by straight or branched alkyl, acyl, or alkoxy, each with up to 7 carbon atoms, or the formula

Base of
(Wherein R _VIII-5 and R _VIII-6 are the same or different and have the meanings previously defined for R _VIII-1 and R _VIII-2 ).
Optionally substituted by:
L _VIII in this case means straight-chain or branched alkoxy with up to 8 carbon atoms or cycloalkyloxy with 3-8 carbon atoms,
T _VIII is the following formula

Means the radical of:
(Wherein R _VIII-7 and R _VIII-8 are the same or different and mean cycloalkyl with 3-8 carbon atoms, or aryl with 6-10 carbon atoms, or S Means a 5- to 7-membered aromatic, optionally benzo-fused, heterocyclic compound with up to 3 heteroatoms from the group N, and / or O, which is up to 3 Times, in the same manner or differently, by trifluoromethyl, trifluoromethoxy, halogen, hydroxy, carboxyl, by straight-chain or branched alkyl, acyl, alkoxy, alkoxy or alkoxycarbonyl with up to 6 carbon atoms each Or optionally substituted by phenyl, phenoxy, or thiophenyl, which is then substituted by halogen, trifluoromethyl, or trifluoromethoxy, or these rings are of the formula

Base of
(Wherein R _VIII-11 and R _VIII-12 are the same or different and have the meanings previously defined for R _VIII-1 and R _VIII-2 ).
Is replaced by
X _VIII means a straight or branched alkyl or alkenyl chain with 2 to 10 carbon atoms each, which is optionally substituted up to 2 times with hydroxy,
R _VIII-9 means hydrogen, and
R _VIII-10 is hydrogen, halogen, azide, trifluoromethyl, hydroxy, mercapto, trifluoromethoxy, straight or branched alkoxy with up to 5 carbon atoms, or a formula

Radicals
(Wherein R _VIII-13 and R _VIII-14 are the same or different and have the meanings previously defined for R _VIII-1 and R _VIII-2 ).
Means
R _VIII-9 and R _VIII-10 together with the carbon atom form a carbonyl group. )].

  The compound of formula VIII is disclosed in WO 9804528, the complete disclosure of which is hereby incorporated by reference.

  Another class of CETP inhibitors that have found utility in the present invention is the formula IX

Consisting of substituted 1,2,4-triazoles and their pharmaceutically acceptable forms having:
Wherein R _IX-1 is selected from higher alkyl, higher alkenyl, higher alkynyl, aryl, aralkyl, aryloxyalkyl, alkoxyalkyl, alkylthioalkyl, arylthioalkyl, and cycloalkylalkyl;
Wherein R _IX-2 is selected from aryl, heteroaryl, cycloalkyl, and cycloalkenyl,
Where R _IX-2 is a substitutable position, alkyl, haloalkyl, alkylthio, alkylsulfinyl, alkylsulfonyl, alkoxy, halo, aryloxy, aralkyloxy, aryl, aralkyl, aminosulfonyl, amino, monoalkylamino and dialkyl Optionally substituted by one or more radicals independently selected from amino; and wherein R _IX-3 is selected from hydride, -SH and halogen;
However, when R _IX-1 is higher alkyl and R _IX-3 is —SH, R _IX-2 cannot be phenyl or 4-methylphenyl. ].

  The compound of formula IX is disclosed in WO 9914204, the full disclosure of which is hereby incorporated by reference.

In a preferred embodiment, the CETP inhibitor is selected from compounds of formula IX:
2,4-dihydro-4- (3-methoxyphenyl) -5-tridecyl-3H-1,2,4-triazole-3-thione;
2,4-dihydro-2- (2-fluorophenyl) -5-tridecyl-3H-1,2,4-triazole-3-thione;
2,4-dihydro-4- (2-methylphenyl) -5-tridecyl-3H-1,2,4-triazole-3-thione;
2,4-dihydro-4- (3-chlorophenyl) -5-tridecyl-3H-1,2,4-triazole-3-thione;
2,4-dihydro-4- (2-methoxyphenyl) -5-tridecyl-3H-1,2,4-triazole-3-thione;
2,4-dihydro-4- (3-methylphenyl) -5-tridecyl-3H-1,2,4-triazole-3-thione;
4-cyclohexyl-2,4-dihydro-5-tridecyl-3H-1,2,4-triazole-3-thione;
2,4-dihydro-4- (3-pyridyl) -5-tridecyl-3H-1,2,4-triazole-3-thione;
2,4-dihydro-4- (2-ethoxyphenyl) -5-tridecyl-3H-1,2,4-triazole-3-thione;
2,4-dihydro-4- (2,6-dimethylphenyl) -5-tridecyl-3H-1,2,4-triazole-3-thione;
2,4-dihydro-4- (4-phenoxyphenyl) -5-tridecyl-3H-1,2,4-triazole-3-thione;
4- (1,3-benzodioxol-5-yl) -2,4-dihydro-5-tridecyl-3H-1,2,4-triazole-3-thione;
4- (2-chlorophenyl) -2,4-dihydro-5-tridecyl-3H-1,2,4-triazole-3-thione;
2,4-dihydro-4- (4-methoxyphenyl) -5-tridecyl-3H-1,2,4-triazole-3-thione;
2,4-dihydro-5-tridecyl-4- (3-trifluoromethylphenyl) -3H-1,2,4-triazole-3-thione;
2,4-dihydro-5-tridecyl-4- (3-fluorophenyl) -3H-1,2,4-triazole-3-thione;
4- (3-chloro-4-methylphenyl) -2,4-dihydro-5-tridecyl-3H-1,2,4-triazole-3-thione;
2,4-dihydro-4- (2-methylthiophenyl) -5-tridecyl-3H-1,2,4-triazole-3-thione;
4- (4-benzyloxyphenyl) -2,4-dihydro-5-tridecyl-3H-1,2,4-triazole-3-thione;
2,4-dihydro-4- (2-naphthyl) -5-tridecyl-3H-1,2,4-triazole-3-thione;
2,4-dihydro-5-tridecyl-4- (4-trifluoromethylphenyl) -3H-1,2,4-triazole-3-thione;
2,4-dihydro-4- (1-naphthyl) -5-tridecyl-3H-1,2,4-triazole-3-thione;
2,4-dihydro-4- (3-methylthiophenyl) -5-tridecyl-3H-1,2,4-triazole-3-thione;
2,4-dihydro-4- (4-methylthiophenyl) -5-tridecyl-3H-1,2,4-triazole-3-thione;
2,4-dihydro-4- (3,4-dimethoxyphenyl) -5-tridecyl-3H-1,2,4-triazole-3-thione;
2,4-dihydro-4- (2,5-dimethoxyphenyl) -5-tridecyl-3H-1,2,4-triazole-3-thione;
2,4-dihydro-4- (2-methoxy-5-chlorophenyl) -5-tridecyl-3H-1,2,4-triazole-3-thione;
4- (4-aminosulfonylphenyl) -2,4-dihydro-5-tridecyl-3H-1,2,4-triazole-3-thione;
2,4-dihydro-5-dodecyl-4- (3-methoxyphenyl) -3H-1,2,4-triazole-3-thione;
2,4-dihydro-4- (3-methoxyphenyl) -5-tetradecyl-3H-1,2,4-triazole-3-thione;
2,4-dihydro-4- (3-methoxyphenyl) -5-undecyl-3H-1,2,4-triazole-3-thione; and
2,4-Dihydro- (4-methoxyphenyl) -5-pentadecyl-3H-1,2,4-triazole-3-thione.

  Another class of CETP inhibitors that have found utility in the present invention is the formula X

Consisting of a hetero-tetrahydroquinoline, an N-oxide of the compound, and their pharmaceutically acceptable forms:
Wherein A _X is cycloalkyl with 3 to 8 carbon atoms or 5- to 7-membered saturation containing up to 3 heteroatoms from the set comprising S, N and / or O. Represents a partially saturated or unsaturated, optionally benzo-fused heterocyclic ring, in which case the saturated heterocyclic ring is attached to and optionally bridged with a nitrogen functional group. As well as the aromatic systems mentioned hereinabove up to 5 times with the same or different substituents in the form of halogen, nitro, hydroxy, trifluoromethyl, trifluoromethoxy, or each with up to 7 carbon atoms. Having linear or branched alkyl, acyl, hydroxyalkyl or alkoxy, or a group of formula -NR _X-3 R _X-4 , wherein R _X-3 and R _X-4 are the same or different; As well as hydrogen, phenyl or a straight or branched chain with up to 6 carbon atoms . Meaning alkyl) by either optionally substituted, or where A _X is the following formula:

Represents the radical of
D _X represents aryl having 6-10 carbon atoms, which is optionally substituted by phenyl, nitro, halogen, trifluoromethyl or trifluoromethoxy, or represented by the formula:

Represents the radical of
Wherein R _X-5 , R _X-6 and R _X-9 are independently of one another cycloalkyl having 3 to 6 carbon atoms, or aryl having 6 to 10 carbon atoms, or Means a 5- to 7-membered aromatic, optionally benzo-fused, saturated or unsaturated mono-, bi-, or tricyclic heterocyclic ring consisting of S, N and / or O Where these rings optionally have halogen, trifluoromethyl, nitro, hydroxy, cyano, carbonyl, trifluoromethoxy, each with up to 6 carbon atoms in the case of nitrogen-containing aromatic rings via the N function. Aryl or trifluoro having 6 to 10 carbon atoms each with up to 5 identical or different substituents in the form of straight or branched acyl, alkyl, alkylthio, alkylalkoxy, alkoxy, or alkoxycarbonyl Methyl-substituted ants Or optionally by a benzo-fused aromatic 5- to 7-membered heterocyclic ring having up to 3 heteroatoms from the set consisting of S, N, and / or O. And / or substituted by the formula -OR _X-10 , -SR _X-11 , SO ₂ R _X-12 or -NR _X-13 R _X-14
(Wherein R _X-10 , R _X-11 , and R _X-12 , independently of one another, mean aryl having 6 to 10 carbon atoms, which is then phenyl, halogen or max. Substituted by up to 2 identical or different substituents in the form of a straight or branched alkyl having 6 carbon atoms,
R _X-13 and R _X-14 are the same or different and have the meanings previously defined for R _X-3 and R _X-4 . ) Or
R _X-5 and R _X-6 are

Means the radical of
R _X-7 means hydrogen or halogen, and
R _X-8 is hydrogen, halogen, azide, trifluoromethyl, hydroxy, trifluoromethoxy, straight or branched alkoxy or alkyl having up to 6 carbon atoms, or the formula —NR _X-15 R _{X -16} radicals,
(Wherein R _X-15 and R _X-16 are the same or different and have the meanings previously defined for R _X-3 and R _X-4 ), or
R _X-7 and R _X-8 together form a radical of formula = O or = NR _X-17 ,
(Wherein R _X-17 represents hydrogen or straight-chain or branched alkyl, alkoxy or acyl having a maximum of 6 carbon atoms),
L _X means a straight or branched alkylene or alkenylene chain having up to 8 carbon atoms, optionally substituted with up to 2 hydroxy groups;
T _X and X _X are the same or different and mean a straight or branched alkylene chain with up to 8 carbon atoms,
Or T _X or X _X denotes a bond,
V _X means an oxygen or sulfur atom or a —NR _X-18 — group, where
R _X-18 is hydrogen or straight or branched alkyl with up to 6 carbon atoms, or phenyl. ),
E _X is a straight chain or branched chain with up to 8 carbon atoms, optionally substituted by cycloalkyl with 3-8 carbon atoms, or cycloalkyl with 3-8 carbon atoms or hydroxy Represents a chain alkyl, or phenyl optionally substituted by halogen or trifluoromethyl,
R _X-1 and R _X-2 together form a linear or branched alkylene chain having up to 7 carbon atoms, which is a carbonyl group and / or

Must be replaced by the radical of:
Where a and b are the same or different and mean a number equal to 1, 2 or 3,
R _X-19 is hydrogen, cycloalkyl with up to 3 carbon atoms, straight or branched silylalkyl with up to 8 carbon atoms, or hydroxyl, with up to 6 carbon atoms Means linear or branched alkyl with up to 8 carbon atoms optionally substituted by linear or branched alkoxy or phenyl, which is then halogen, nitro, trifluoromethyl Substituted with alkyl, optionally substituted with a group of formula -OR _X-22 , trifluoromethoxy, or phenyl, or tetrazole-substituted phenyl, and a group of formula -OR _X-22 ;
(Wherein R _X-22 means straight or branched acyl with up to 4 carbon atoms or benzyl), or
R _X-19 means linear or branched acyl with up to 20 carbon atoms or benzoyl, optionally substituted by halogen, trifluoromethyl, nitro or trifluoromethoxy, or Mean straight or branched fluoroacyl with up to 8 carbon atoms and 9 fluorine atoms,
R _X-20 and R _X-21 are the same or different and represent hydrogen, phenyl or straight-chain or branched alkyl with up to 6 carbon atoms, or
R _X-20 and R _X-21 together form a 3- to 6-membered carbocyclic ring, and the formed monocyclic ring is optionally also geminal, each of 3 to 7 Up to 6 carbon atoms, each with up to 6 identical or different substituents in the form of trifluoromethyl, hydroxy, nitrile, halogen, carboxyl, nitro, azide, cyano, cycloalkyl or cycloalkyloxy with carbon atoms Optionally substituted by linear or branched alkoxycarbonyl, alkoxy or alkylthio with or by linear or branched alkyl with up to 6 carbon atoms, which in turn has a maximum of 2 hydroxyls , Benzyloxy, trifluoromethyl, benzoyl, straight or branched alkoxy with up to 4 carbon atoms each, oxyacyl or carbonyl, and / or phenyl May be substituted identically or differently, which may then be substituted by halogen, trifluoromethyl or trifluoromethoxy, and / or the carbocyclic ring formed is also geminally phenyl, benzoyl, thiophenyl Or optionally substituted by up to 5 identical or different substituents in the form of sulfonylbenzyl, which are then optionally substituted by halogen, trifluoromethyl, trifluoromethoxy or nitro and / or optional The following formula

Is replaced by:
(Wherein c is a number equal to 1, 2, 3 or 4;
d means a number equal to 0 or 1;
R _X-23 and R _X-24 are the same or different and are hydrogen, cycloalkyl with 3 to 6 carbon atoms, linear or branched alkyl with up to 6 carbon atoms, up to 2 Benzyl or phenyl optionally substituted the same or different by halogen, trifluoromethyl, cyano, phenyl or nitro, and / or the carbocyclic ring formed is optionally

Is replaced by a spiro-linked radical of:
Here, W _X means an oxygen or sulfur atom,
Y _X and Y ′ _X together form a 2-6 membered linear or branched alkylene chain;
e means a number equal to 1, 2, 3, 4, 5, 6, or 7;
f means a number equal to 1 or 2,
R _X-25 , R _X-26 , R _X-27 , R _X-28 , R _X-29 , R _X-30 and R _X-31 are the same or different and are hydrogen, trifluoromethyl, phenyl, halogen, Or linear or branched alkyl or alkoxy each with up to 6 carbon atoms,
Or R _X-25 and R _X-26 , or R _X-27 and R _X-28 each together form a straight or branched alkyl chain with up to 6 carbon atoms,
Or R _X-25 and R _X-26 , or R _X-27 and R _X-28 are each represented by the following formulae:

Forms radicals of:
(W _X has the meaning indicated above,
g means a number equal to 1, 2, 3, 4, 5, 6, or 7. ),
R _X-32 and R _X-33 together form a 3- to 7-membered heterocycle, which contains an oxygen or sulfur atom, or a group of formula SO, SO ₂ or π-NR _X-34 . Inclusive, R _X-34 means hydrogen, phenyl, benzyl, or straight or branched alkyl with up to 4 carbon atoms. )].

  The compound of formula X is disclosed in WO 9914215, which is fully incorporated herein by reference.

In a preferred embodiment, the CETP inhibitor is selected from compounds of formula X:
2-cyclopentyl-5-hydroxy-7,7-dimethyl-4- (3-thienyl) -3- (4-trifluoromethylbenxoyl) -5,6,7,8-tetrahydroquinoline;
2-cyclopentyl-3- [fluoro- (4-trifluoromethylphenyl) methyl] -5-hydroxy-7,7-dimethyl-4- (3-thienyl) -5,6,7,8-tetrahydroquinoline; and
2-Cyclopentyl-5-hydroxy-7,7-dimethyl-4- (3-thienyl) -3- (trifluoromethylbenxyl) -5,6,7,8-tetrahydroquinoline.

  Another class of CETP inhibitors that have found utility in the present invention is the formula XI

Consisting of substituted tetrahydronaphthalene and analog compounds and their pharmaceutically acceptable forms having:
Wherein A _XI means cycloalkyl with 3 to 8 carbon atoms, or aryl with 6 to 10 carbon atoms, or a set of S, N and / or O Means a 5- to 7-membered, saturated, partially unsaturated or unsaturated, benzo-fused, heterocycle with up to 4 heteroatoms from The aforementioned aryl and heterocyclic ring systems are cyano, halogen, nitro, carboxyl, hydroxy, trifluoromethyl, trifluoro-methoxy, or straight or branched alkyl with up to 7 carbon atoms each, By acyl, hydroxyalkyl, alkylthio, alkoxycarbonyl, oxyalkoxycarbonyl or alkoxy, or

Is substituted the same or different up to 5 times by
(Wherein R _XI-3 and R _XI-4 are the same or different and mean hydrogen, phenyl, or straight or branched alkyl with up to 6 carbon atoms),
D _XI is the following formula

Means the radical of:
(Wherein R _XI-5 , R _XI-6 and R _XI-9 independently of one another refer to cycloalkyl with 3 to 6 carbon atoms or with 6 to 10 carbon atoms Means aryl with or 5- to 7-membered, benzo-fused, saturated or unsaturated, with up to 4 heteroatoms of the set S, N and / or O Means mono-, bi- or tricyclic heterocycles, where these rings are nitrogen-containing rings via an N-functional group, up to 5 times, the same or different, halogen, trifluoromethyl, 6-10 carbons each by nitro, hydroxy, cyano, carboxyl, trifluoromethoxy, straight or branched acyl, alkyl, alkylthio, alkylalkoxy, alkoxy or alkoxycarbonyl with up to 6 carbon atoms each Aryl or trifluoromethyl with atoms Substituted by a substituted aryl or by an aromatic 5- to 7-membered heterocycle that may be benzo-fused with up to 3 heteroatoms in the S, N and / or O pair And / or the following formula

Is replaced by the group:
(Wherein R _XI-10 , R _XI-11 , and R _XI-12 independently of one another refer to aryl with 6-10 carbon atoms, which itself is the same up to 2 times Or as substituted, phenyl, halogen, or straight-chain or branched alkyl with up to 6 carbon atoms,
R _XI-13 and R _X-14 are the same or different and have the meanings given above for R _XI-3 and R _X-4 . ),
Or, R _XI-5 and / or R _XI-6 is represented by the following formula:

Means the radical of:
R _XI-7 means hydrogen, halogen or methyl, and
R _XI-8 is hydrogen, halogen, azide, trifluoromethyl, hydroxy, trifluoromethoxy, straight or branched alkoxy or alkyl with up to 6 carbon atoms each, or the formula —NR _XI-15 R Means _X-16 radical,
(Wherein R _XI-15 and R _XI-16 are the same or different and have the meanings indicated above for R _XI-3 and R _X-4 ), or
R _XI-7 and R _XI-8 together form a radical of the formula = O or = NR _X-17 (where R _X-17 is a hydrogen or a straight chain with up to 6 carbon atoms each. Meaning chain or branched alkyl, alkoxy or acyl).
L _XI means a straight-chain or branched alkylene- or alkenylene chain, each with up to 8 carbon atoms, which is probably replaced by hydroxy up to twice,
T _XI and X _XI are the same or different and mean a straight or branched alkylene chain with up to 8 carbon atoms,
Or, T _XI and X _XI mean a bond,
V _XI means an oxygen- or sulfur atom, or a -NR _XI-18 group, where R _XI-18 is hydrogen or a straight or branched chain with up to 6 carbon atoms Chain alkyl or phenyl)),
E _XI means a cycloalkyl with 3 to 8 carbon atoms, or a straight chain with up to 8 carbon atoms, possibly substituted by cycloalkyl or hydroxy with 3 to 8 carbon atoms Or a branched alkyl, or phenyl, possibly substituted by halogen or trifluoromethyl,
R _XI-1 and R _XI-2 together form a linear or branched alkylene chain with up to 7 carbon atoms, which is a carbonyl group and / or

Must be replaced by the radical of:
Where a and b are the same or different and mean a number of 1, 2 or 3,
R _XI-19 is hydrogen, cycloalkyl with 3-7 carbon atoms, straight chain or branched silylalkyl with up to 8 carbon atoms, or straight chain with up to 8 carbon atoms or Means branched alkyl, which is probably substituted by hydroxy, straight or branched alkoxy with up to 6 carbon atoms or by halogen, nitro, trifluoromethyl, trifluoromethoxy per se Substituted by phenyl obtained or by phenyl substituted by phenyl or tetrazole, and alkyl is probably substituted by the formula -OR _XI-22 ,
(Wherein R _XI-22 means straight or branched acyl with up to 4 carbon atoms, or benzyl),
Or, R _XI-19 means a straight or branched acyl or benzoyl with up to 20 carbon atoms, possibly substituted by halogen, trifluoromethyl, nitro or trifluoromethoxy, or up to Means straight or branched fluoroacyl with 8 carbon atoms and 9 fluorine atoms,
R _XI-20 and R _XI-21 are the same or different and represent hydrogen, phenyl or straight-chain or branched alkyl with up to 6 carbon atoms;
Or R _XI-20 and R _XI-21 together form a 3- to 6-membered carbocycle, and possibly also geminal, the alkylene chain formed by R _XI-1 and R _XI-2 is Probably up to 6 times, the same or different, each up to 6 with trifluoromethyl, hydroxy, nitrile, halogen, carboxyl, nitro, azide, cyano, cycloalkyl or cycloalkyloxy with 3-7 carbon atoms each Is substituted by straight or branched alkoxycarbonyl, alkoxy or alkoxythio with 5 carbon atoms or by straight or branched alkyl with up to 6 carbon atoms, which itself is Up to 2 times, the same or different, hydroxyl, benzyloxy, trifluoromethyl, benzoyl, straight or branched alkoxy, oxyacid with up to 4 carbon atoms each The alkylene chain formed by R _XI-1 and R _{XI-2 is} substituted by phenyl which can be substituted by halogen, trifluoromethyl or trifluoromethoxy; , Also geminal, possibly up to 5 times, the same or different, substituted by phenyl, benzoyl, thiophenyl, or sulfobenzyl, which themselves are probably substituted by halogen, trifluoromethyl, trifluoromethoxy or nitro, and / or R _The alkylene chain formed by _XI-1 and _RXI-2 probably has the formula

Is replaced by a radical of:
Where c means the number 1, 2, 3 or 4;
d means the number 0 or 1,
R _XI-23 and R _XI-24 are the same or different and are hydrogen, cycloalkyl with 3 to 6 carbon atoms, linear or branched alkyl with up to 6 carbon atoms, possibly up to 2 Times the same or different, meaning benzyl or phenyl substituted by halogen, trifluoromethyl, cyano, phenyl or nitro, and / or the alkylene chain formed by R _XI-1 and R _XI-2 is probably Following formula

Is replaced by a spiro-bonded radical of:
W _XI means either oxygen or sulfur atom,
Y _XI and Y ′ _XI together form a 2- to 6-membered linear or branched alkylene chain;
e is a number of 1, 2, 3, 4, 5, 6 or 7,
f is a number of 1 or 2,
R _XI-25 , R _XI-26 , R _XI-27 , R _XI-28 , R _XI-29 , R _XI-30 and R _XI-31 are the same or different and are hydrogen, trifluoromethyl, phenyl, halogen, Or linear or branched alkyl or alkoxy each with up to 6 carbon atoms,
Or R _XI-25 and R _XI-26 , or R _XI-27 and R _XI-28 each together form a linear or branched alkyl chain with up to 6 carbon atoms,
Or R _XI-25 and R _XI-26 , or R _XI-27 and R _XI-28 are

Forms radicals of:
(W _X has the meaning indicated above,
g means a number equal to 1, 2, 3, 4, 5, 6, or 7. ),
R _XI-32 and R _XI-33 together form a 3- to 7-membered heterocycle, which contains an oxygen or sulfur atom, or a group of formula SO, SO ₂ or —NR _XI-34 ,
R _XI-34 here means hydrogen, phenyl, benzyl or straight-chain or branched alkyl with up to 4 carbon atoms. ].

  The compound of formula XI is disclosed in WO 9914174, the full disclosure of which is hereby incorporated by reference.

  Another class of CETP inhibitors that find utility in the present invention is the formula XII

Consisting of 2-aryl-substituted pyridines and their pharmaceutically acceptable forms:
Wherein A _XII and E _XII are the same or different, and possibly the same or different up to 5 times, with halogen, hydroxy, trifluoromethyl, trifluoromethoxy, nitro, or each with up to 7 carbon atoms. Means aryl with 6-10 carbon atoms, substituted by linear or branched alkyl, acyl, hydroxyalkyl or alkoxy with or by a group of formula -NR _XII-1 R _XII-2 ,
(Wherein R _XII-1 and R _XII-2 are the same or different and are hydrogen, phenyl or straight-chain or branched alkyl with up to 6 carbon atoms),
D _XII means straight-chain or branched alkyl with up to 8 carbon atoms, which is substituted by hydroxy,
L _XII means cycloalkyl with 3-8 carbon atoms, or straight chain or branched alkyl with up to 8 carbon atoms, which is probably 3-8 carbons Substituted by cycloalkyl with an atom or by hydroxy;
T _XII has the formula R _XII-3 -X _XII -or

Means the radical of
Where R _XII-3 and R _XII-4 are the same or different and mean cycloalkyl with 3-8 carbon atoms, or aryl with 6-10 carbon atoms, or S, N And / or a 5- to 7-membered aromatic, potentially benzo-fused heterocycle with up to 3 heteroatoms from the O pair, possibly the same up to 3 times Or, alternatively, by trifluoromethyl, trifluoromethoxy, halogen, hydroxy, carboxyl, nitro, by straight or branched alkyl, acyl, alkoxy or alkoxycarbonyl with up to 6 carbon atoms each, or by phenyl, phenoxy Or substituted by phenylthio, which is then substituted by halogen, trifluoromethyl or trifluoromethoxy, and / or where these rings are probably Substituted by a group of _{-NR XII-7 R XII-8} ,
(Wherein R _XII-7 and R _XII-8 are the same or different and have the same meaning as R _XII-1 and R _XII-2 shown above),
X _XII is a linear or branched alkyl or alkenyl, each with 2-10 carbon atoms, possibly substituted by hydroxy or halogen, up to twice,
R _XII-5 means hydrogen,
R _XII-6 is hydrogen, halogen, mercapto, azide, trifluoromethyl, hydroxy, trifluoromethoxy, linear or branched alkoxy with up to 5 carbon atoms, or the formula —NR _XII-9 R _XII Means _-10 radicals,
(Wherein R _XII-9 and R _XII-10 are the same or different and have the same meaning as R _XII-1 and R _XII-2 shown above),
Alternatively, R _XII-5 and R _XII-6 together with the carbon atom form a carbonyl group. ].

  The compound of formula XII is disclosed in EP 796846-A1, the complete disclosure of which is incorporated herein by reference.

In a preferred embodiment, the CETP inhibitor is selected from compounds of formula XII:
4,6-bis- (p-fluorophenyl) -2-isopropyl-3-[(p-trifluoromethylphenyl)-(fluoro) -methyl] -5- (1-hydroxyethyl) pyridine;
2,4-bis- (4-fluorophenyl) -6-isopropyl-5- [4- (trifluoromethylphenyl) -fluoromethyl] -3-hydroxymethyl) pyridine; and
2,4-bis- (4-fluorophenyl) -6-isopropyl-5- [2- (3-trifluoromethylphenyl) vinyl] -3-hydroxymethyl) pyridine.

  Another class of CETP inhibitors that have found utility in the present invention is the formula XIII

And the pharmaceutically acceptable forms thereof:
[Wherein R _XIII is linear or branched C _1-10 alkyl; linear or branched C _2-10 alkenyl; halogenated C _1-4 lower alkyl; optionally substituted C _3-10 cycloalkyl; _optionally substituted C _5-8 cycloalkenyl; _optionally substituted C _3-10 cycloalkyl C _1-10 alkyl; _optionally substituted aryl; optionally substituted aralkyl; Or a 5- or 6-membered heterocyclic group having 1 to 3 nitrogen atoms, oxygen atoms or sulfur atoms, which may be substituted,
X _XIII-1 , _XXIII-2 , _XXIII-3 and _XXIII-4 are the same or different and are a hydrogen atom; halogen atom; C _1-4 lower alkyl; halogenated C _1-4 lower alkyl; C _1-4 lower alkoxy; each cyano group; nitro group; acyl; or aryl;
Y _XIII is —CO—; or —SO ₂ —; and
Z _XIII is a hydrogen atom; or a mercapto protecting group. ].

  The compound of formula XIII is disclosed in WO 98/35937, the full disclosure of which is incorporated herein by reference.

In a preferred embodiment, the CETP inhibitor is selected from compounds of formula XIII:
N, N '-(dithiodi-2,1-phenylene) bis [2,2-dimethyl-propanamide];
N, N ′-(dithiodi-2,1-phenylene) bis [1-methyl-cyclohexanecarboxamide];
N, N ′-(dithiodi-2,1-phenylene) bis [1- (3-methylbutyl) -cyclopentanecarboxamide];
N, N ′-(dithiodi-2,1-phenylene) bis [1- (3-methylbutyl) -cyclohexanecarboxamide];
N, N ′-(dithiodi-2,1-phenylene) bis [1- (2-ethylbutyl) -cyclohexanecarboxamide];
N, N '-(dithiodi-2,1-phenylene) bis-tricyclo [3.3.1.1 ^3,7 ] decane-1-carboxamide;
Propanethioic acid, 2-methyl-, S- [2 [[[1- (2-ethylbutyl) cyclohexyl] carbonyl] amino] phenyl] ester;
Propanethioic acid, 2,2-dimethyl-, S- [2-[[[1- (2-ethylbutyl) cyclohexyl] carbonyl] amino] phenyl] ester; and ethanethioic acid, S- [2-[[[1 -(2-Ethylbutyl) cyclohexyl] carbonyl] amino] phenyl] ester.

  Another class of CETP inhibitors that have found utility in the present invention is the formula XIV

Consisting of polycyclic aryl and heteroaryl tertiary-heteroalkylamines and their pharmaceutically acceptable forms having:
[Where n _XIV Is an integer selected from 0 to 5;
R _XIV-1 Is selected from the group consisting of haloalkyl, haloalkenyl, haloalkoxyalkyl, and haloalkenyloxyalkyl;
X _XIV Is selected from the group consisting of O, H, F, S, S (O), NH, N (OH), N (alkyl), and N (alkoxy);
R _XIV-16 Is hydride, alkyl, alkenyl, alkynyl, aryl, aralkyl, aryloxyalkyl, alkoxyalkyl, alkenyloxyalkyl, alkylthioalkyl, arylthioalkyl, aralkoxyalkyl, heteroaralkoxyalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl , Cycloalkyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkenyl, cycloalkenylalkyl, haloalkyl, haloalkenyl, halocycloalkyl, halocycloalkenyl, haloalkoxyalkyl, haloalkenyloxyalkyl, halocycloalkoxyalkyl, halocycloalkenyloxy Alkyl, perhaloaryl, perhaloaralkyl, perhaloaryloxyalkyl, f Roaryl, heteroarylalkyl, monocarboalkoxyalkyl, monocarboalkoxy, dicarboalkoxyalkyl, monocarboxamide, monocyanoalkyl, dicyanoalkyl, carboalkoxycyanoalkyl, acyl, aroyl, heteroaroyl, heteroaryloxyalkyl, dialkoxyphospho Noalkyl, trialkylsilyl, and R to form a heterocyclic ring with 5-10 adjacent members _XIV-4 , R _XIV-8 , R _XIV-9 And R _XIV-13 Selected from the group consisting of a spacer selected from the group consisting of a covalent single bond linked to the point of attachment of an aromatic substituent selected from the group consisting of and a linear spacer moiety having 1 to 4 adjacent atoms, Where R _XIV-2 When is an alkyl, the spacer moiety is other than a covalent single bond, and when X is H or F, R _XIV-16 Does not exist;
D _XIV-1 , D _XIV-2 , J _XIV-1 , J _XIV-2 And K _XIV-1 Is independently selected from the group consisting of C, N, O, S and a covalent bond, provided that D _XIV-1 , D _XIV-2 , J _XIV-1 , J _XIV-2 And K _XIV-1 Only one of is a covalent bond and D _XIV-1 , D _XIV-2 , J _XIV-1 , J _XIV-2 And K _XIV-1 Only 1 of O is O and D _XIV-1 , D _XIV-2 , J _XIV-1 , J _XIV-2 And K _XIV-1 Only one of S is S and D _XIV-1 , D _XIV-2 , J _XIV-1 , J _XIV-2 And K _XIV-1 D if two of O and S are _XIV-1 , D _XIV-2 , J _XIV-1 , J _XIV-2 And K _XIV-1 Must be covalently bonded, as well as D _XIV-1 , D _XIV-2 , J _XIV-1 , J _XIV-2 And K _XIV-1 Only 4 of them are N;
D _XIV-3 , D _XIV-4 , J _XIV-3 , J _XIV-4 And K _XIV-2 Is independently selected from the group consisting of C, N, O, S and a covalent bond, provided that D _XIV-3 , D _XIV-4 , J _XIV-3 , J _XIV-4 And K _XIV-2 Only one of is a covalent bond and D _XIV-3 , D _XIV-4 , J _XIV-3 , J _XIV-4 And K _XIV-2 Only 1 of O is O and D _XIV-3 , D _XIV-4 , J _XIV-3 , J _XIV-4 And K _XIV-2 Only one of S is S and D _XIV-3 , D _XIV-4 , J _XIV-3 , J _XIV-4 And K _XIV-2 If two of O and S are D _XIV-3 , D _XIV-4 , J _XIV-3 , J _XIV-4 And K _XIV-2 Must be covalently bonded, as well as D _XIV-3 , D _XIV-4 , J _XIV-3 , J _XIV-4 And K _XIV-2 Only 4 of them are covalent bonds;
R _XIV-2 Is hydride, hydroxy, hydroxyalkyl, amino, aminoalkyl, alkylamino, dialkylamino, alkyl, alkenyl, alkynyl, aryl, aralkyl, aralkoxyalkyl, aryloxyalkyl, alkoxyalkyl, heteroaryloxyalkyl, alkenyloxyalkyl , Alkylthioalkyl, aralkylthioalkyl, arylthioalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkenyl, cycloalkenylalkyl, haloalkyl, haloalkenyl, halocycloalkyl, halocycloalkenyl, haloalkoxy, alloalkoxyalkyl, Haloalkenyloxyalkyl, halocycloalkoxy, halocycloalkoxyalkyl, halocycloa Kenyloxyalkyl, perhaloaryl, perhaloaralkyl, perhaloaryloxyalkyl, heteroaryl, heteroarylalkyl, heteroarylthioalkyl, heteroaralkylthioalkyl, monocarboalkoxyalkyl, dicarboalkoxyalkyl, monocyanoalkyl, Dicyanoalkyl, carboalkoxycyanoalkyl, alkylsulfinyl, alkylsulfonyl, alkylsulfinylalkyl, alkylsulfonylalkyl, haloalkylsulfinyl, haloalkylsulfonyl, arylsulfinyl, arylsulfinylalkyl, arylsulfonyl, arylsulfonylalkyl, aralkylsulfinyl, aralkylsulfonyl, cycloalkyl Sulfinyl, cycloalkylsulfoni , Cycloalkylsulfinylalkyl, cycloalkylsulfonylalkyl, heteroarylsulfonylalkyl, heteroarylsulfinyl, heteroarylsulfonyl, heteroarylsulfinylalkyl, aralkylsulfinylalkyl, aralkylsulfonylalkyl, carboxy, carboxyalkyl, carboalkoxy, carboxyamide, carboxyamide Independently selected from the group consisting of alkyl, carboaralkoxy, dialkoxyphosphono, dialalkoxyphosphono, dialkoxyphosphonoalkyl, and dialalkoxyphosphonoalkyl;
R _XIV-2 And R _XIV-3 Together form a ring selected from cycloalkyl having 3 to 8 members, cycloalkenyl having 5 to 8 members, and heterocyclic having 4 to 8 members. Forming a linear spacer moiety selected from the group consisting of a moiety having a covalent single bond and 1 to 6 adjacent atoms;
R _XIV-3 Is hydride, hydroxy, halogen, cyano, aryloxy, hydroxyalkyl, amino, alkylamino, dialkylamino, acyl, sulfhydryl, acylamide, alkoxy, alkylthio, arylthio, alkyl, alkenyl, alkynyl, aryl, aralkyl, aryloxyalkyl, Alkoxyalkyl, heteroarylthio, aralkylthio, aralkoxyalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl, aroyl, heteroaroyl, aralkylthioalkyl, heteroaralkylthioalkyl, heteroaryloxyalkyl, alkenyloxyalkyl, alkylthioalkyl, arylthio Alkyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkenyl, cycl Alkenyl, cycloalkenylalkyl, haloalkyl, haloalkenyl, halocycloalkyl, halocycloalkenyl, haloalkoxy, haloalkoxyalkyl, haloalkoxyoxyalkyl, halocycloalkoxy, halocycloalkoxyalkyl, halocycloalkenyloxyalkyl, perhaloaryl, Perhaloaralkyl, perhaloaryloxyalkyl, heteroaryl, heteroarylalkyl, heteroarylthioalkyl, monocarboalkoxyalkyl, dicarboalkoxyalkyl, monocyanoalkyl, dicyanoalkyl, carboalkoxycyanoalkyl, alkylsulfinyl, alkylsulfonyl, Haloalkylsulfinyl, haloalkylsulfonyl, arylsulfinyl, arylsulfin Alkyl, arylsulfonyl, arylsulfonylalkyl, aralkylsulfinyl, aralkylsulfonyl, cycloalkylsulfinyl, cycloalkylsulfonyl, cycloalkylsulfinylalkyl, cycloalkylsulfonylalkyl, heteroarylsulfonylalkyl, heteroarylsulfinyl, heteroarylsulfonyl, heteroarylsulfinylalkyl , Aralkylsulfinylalkyl, aralkylsulfonylalkyl, carboxy, carboxyalkyl, carboalkoxy, carboxyamide, carboxyamidoalkyl, carboaralkoxy, dialkoxyphosphono, dialalkoxyphosphono, dialkoxyphosphonoalkyl, and dialalkoxy Selected from the group consisting of phosphonoalkyl;
Y _XIV Is a covalent single bond, (C (R _XIV-14 ) ₂ ) _qXIV (Where qXIV is selected from an integer of 1 and 2), and (CH (R _XIV-14 )) _gXIV -W _XIV -(CH (R _XIV-14 )) _pXIV (Where gXIV and pXIV are integers independently selected from 0 and 1);
R _XIV-14 Is hydrido, hydroxy, halogen, cyano, aryloxy, amino, alkylamino, dialkylamino, hydroxyalkyl, acyl, aroyl, heteroaroyl, heteroaryloxyalkyl, sulfhydryl, acylamide, alkoxy, alkylthio, arylthio, alkyl, alkenyl, alkynyl , Aryl, aralkyl, aryloxyalkyl, aralkoxyalkylalkoxy, alkylsulfinylalkyl, alkylsulfonylalkyl, aralkylthioalkyl, heteroaralkoxythioalkyl, alkoxyalkyl, heteroaryloxyalkyl, alkenyloxyalkyl, alkylthioalkyl, aryl Ruthioalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkenyl Cycloalkenyl, cycloalkenylalkyl, haloalkyl, haloalkenyl, halocycloalkyl, halocycloalkenyl, haloalkoxy, haloalkoxyalkyl, haloalkoxyoxyalkyl, halocycloalkoxy, halocycloalkoxyalkyl, halocycloalkenyloxyalkyl, perhaloaryl Perhaloaralkyl, perhaloaryloxyalkyl, heteroaryl, heteroarylalkyl, heteroarylthioalkyl, heteroaralkylthioalkyl, monocarboalkoxyalkyl, dicarboalkoxyalkyl, monocyanoalkyl, dicyanoalkyl, carboalkoxycyanoalkyl, Alkylsulfinyl, alkylsulfonyl, haloalkylsulfinyl, haloalkylsulfonyl, Sulfinyl, arylsulfinylalkyl, arylsulfonyl, arylsulfonylalkyl, aralkylsulfinyl, aralkylsulfonyl, cycloalkylsulfinyl, cycloalkylsulfonyl, cycloalkylsulfinylalkyl, cycloalkylsulfonylalkyl, heteroarylsulfonylalkyl, heteroarylsulfinyl, heteroarylsulfonyl, Heteroarylsulfinylalkyl, aralkylsulfinylalkyl, aralkylsulfonylalkyl, carboxy, carboxyalkyl, carboalkoxy, carboxyamide, carboxyamidoalkyl, carboaralkoxy, dialkoxyphosphono, dialalkoxyphosphono, dialkoxyphosphonoalkyl, Diaralkoxyphosphonoa R to form a ring selected from the group consisting of rualkyl, a cycloalkenyl ring having 5-8 adjacent members and a heterocyclic ring having 5-8 adjacent members _XIV-9 And R _XIV-13 A spacer selected from a moiety having a chain length of 3-6 atoms connected to a point of attachment selected from the group consisting of: and R to form a heterocyclic ring having 5-8 adjacent members _XIV-4 And R _XIV-8 Independently selected from the group consisting of spacers selected from the group consisting of moieties having a chain length of 2-5 atoms linked to a bond point selected from the group consisting of Y, _XIV R is a covalent bond _XIV-14 Substituent is Y _XIV Not bound to;
R _XIV-14 And R _XIV-14 Together are covalent bonds, alkylenes, haloalkylenes, and saturated cycloalkyls with 5-8 neighbors, cycloalkenyls with 5-8 neighbors, and when attached to different atoms, and Selected from the group consisting of spacers selected from the group consisting of moieties having 2 to 5 atoms in chain length connected to form a ring selected from a heterocycle having 5 to 8 neighboring members Forming a group;
R _XIV-14 And R _XIV-14 Together are oxo, thiono, alkylene, haloalkylene, and cycloalkyl with 4 to 8 members, cycloalkenyl with 4 to 8 members, and 4 when attached to the same atom A group selected from the group consisting of spacers selected from the group consisting of moieties having 3 to 7 atoms in chain length connected to form a ring selected from a heterocycle having ˜8 adjacent members Forming;
W _XIV Are O, C (O), C (S), C (O) N (R _XIV-14 ), C (S) N (R _XIV-14 ), (R _XIV-14 ) NC (O), (R _XIV-14 NC (S), S, S (O), S (O) ₂ , S (0) ₂ N (R _XIV-14 ), (R _XIV-14 NS (O) ₂ , And N (R _XIV-14 ) Selected from the group consisting of R _XIV-14 Is selected from other than halogen and cyano;
Z _XIV Is a covalent single bond, (C (R _XIV-15 ) ₂ ) _qXIV-2 (Where qXIV-2 is an integer selected from 1 and 2), (CH (R _XIV-15 )) _jXIV -W- (CH (R _XIV-15 )) _kXIV (Where jXIV and kXIV are integers independently selected from 0 and 1), selected independently from the group consisting of Z _XIV R is a covalent single bond _XIV-15 Substituent is Z _XIV Not bound to;
R _XIV-15 Z _XIV (C (R _XIV-15 ) ₂ ) _qXIV-2 (Where qXIV-2 is an integer selected from 1 and 2), hydrido, hydroxy, halogen, cyano, aryloxy, amino, alkylamino, dialkylamino, hydroxyalkyl, acyl, Aroyl, heteroaroyl, heteroaryloxyalkyl, sulfhydryl, acylamide, alkoxy, alkylthio, arylthio, alkyl, alkenyl, alkynyl, aryl, aralkyl, aryloxyalkyl, aralkoxyalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl, aralkylthioalkyl, Heteroaralkylthioalkyl, alkoxyalkyl, heteroaryloxyalkyl, alkenyloxyalkyl, alkylthioalkyl, arylthioalkyl, cycloalkyl, Chloroalkyl, cycloalkylalkenyl, cycloalkenyl, cycloalkenylalkyl, haloalkyl, haloalkenyl, halocycloalkyl, halocycloalkenyl, haloalkoxy, haloalkoxyalkyl, haloalkenyloxyalkyl, halocycloalkoxy, halocycloalkoxyalkyl, halo Cycloalkenyloxyalkyl, perhaloaryl, perhaloaralkyl, perhaloaryloxyalkyl, heteroaryl, heteroarylalkyl, heteroarylthioalkyl, heteroaralkylthioalkyl, monocarboalkoxyalkyl, dicarboalkoxyalkyl, monocyanoalkyl, Dicyanoalkyl, carboalkoxycyanoalkyl, alkylsulfinyl, alkylsulfonyl, haloa Killsulfinyl, haloalkylsulfonyl, arylsulfinyl, arylsulfinylalkyl, arylsulfonyl, arylsulfonylalkyl, aralkylsulfinyl, aralkylsulfonyl, cycloalkylsulfinyl, cycloalkylsulfonyl, cycloalkylsulfinylalkyl, cycloalkylsulfonylalkyl, heteroarylsulfonylalkyl, hetero Arylsulfinyl, heteroarylsulfonyl, heteroarylsulfinylalkyl, aralkylsulfinylalkyl, aralkylsulfonylalkyl, carboxy, carboxyalkyl, carboalkoxy, carboxyamide, carboxyamidoalkyl, carboaralkoxy, dialkoxyphosphono, dialalkoxyphosphono , Dial To form a ring selected from the group consisting of xyphosphonoalkyl, dialalkoxyphosphonoalkyl, cycloalkenyl ring having 5-8 adjacent members and heterocyclic ring having 5-8 adjacent members R _XIV-4 And R _XIV-8 A spacer selected from a moiety having a chain length of 3-6 atoms connected to a point of attachment selected from the group consisting of: and R to form a heterocyclic ring having 5-8 adjacent members _XIV-9 And R _XIV-13 Independently selected from the group consisting of spacers selected from moieties having a chain length of 2-5 atoms linked to a point of attachment selected from the group consisting of:
R _XIV-15 And R _XIV-15 Together are covalent bonds, alkylenes, haloalkylenes, and saturated cycloalkyls with 5-8 neighbors, cycloalkenyls with 5-8 neighbors, and when attached to different atoms, and A group consisting of a spacer selected from the group consisting of moieties having 2 to 5 atoms in chain length connected to form a ring selected from the group consisting of heterocyclic groups having 5 to 8 adjacent members Forming a group selected from;
R _XIV-15 And R _XIV-15 Together are oxo, thiono, alkylene, haloalkylene, and cycloalkyl with 4 to 8 members, cycloalkenyl with 4 to 8 members, and 4 when attached to the same atom A group selected from the group consisting of spacers selected from the group consisting of moieties having 3 to 7 atoms in chain length connected to form a ring selected from a heterocycle having ˜8 adjacent members Forming;
R _XIV-15 Z _XIV Is (CH (R _XIV-15 )) _jXIV -W- (CH (R _XIV-15 )) _kXIV (Wherein jXIV and kXIV are integers independently selected from 0 and 1), hydrido, halogen, cyano, aryloxy, carboxyl, acyl, aroyl, heteroaroyl, hydroxyalkyl, heteroaryl Oxyalkyl, acylamide, alkoxy, alkylthio, arylthio, alkyl, alkenyl, alkynyl, aryl, aralkyl, aryloxyalkyl, alkoxyalkyl, heteroaryloxyalkyl, aralkoxyalkyl, heteroaralkoxyalkyl, alkylsulfonylalkyl, alkylsulfinyl Alkyl, alkenyloxyalkyl, alkylthioalkyl, arylthioalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkenyl, cycl Alkenylalkyl, haloalkyl, haloalkenyl, halocycloalkyl, halocycloalkenyl, haloalkoxy, haloalkoxyalkyl, haloalkenyloxyalkyl, halocycloalkoxy, halocycloalkoxyalkyl, halocycloalkenyloxyalkyl, perhaloaryl, perhaloaralkyl , Perhaloaryloxyalkyl, heteroaryl, heteroarylalkyl, heteroarylthioalkyl, heteroaralkylthioalkyl, monocarboalkoxyalkyl, dicarboalkoxyalkyl, monocyanoalkyl, dicyanoalkyl, carboalkoxycyanoalkyl, alkylsulfinyl, alkyl Sulfonyl, haloalkylsulfinyl, haloalkylsulfonyl, arylsulfinyl, ali Rusulfinylalkyl, arylsulfonyl, arylsulfonylalkyl, aralkylsulfinyl, aralkylsulfonyl, cycloalkylsulfinyl, cycloalkylsulfonyl, cycloalkylsulfinylalkyl, cycloalkylsulfonylalkyl, heteroarylsulfonylalkyl, heteroarylsulfinyl, heteroarylsulfonyl, heteroaryl Sulfinylalkyl, aralkylsulfinylalkyl, aralkylsulfonylalkyl, carboxyalkyl, carboalkoxy, carboxyamide, carboxyamidoalkyl, carboaralkoxy, dialkoxyphosphonoalkyl, dialalkoxyphosphonoalkyl, 5-8 adjacent members Having a cycloalkenyl ring and a heterocycle having 5 to 8 adjacent members R to form a ring selected from the group consisting of ring _XIV-4 And R _XIV-8 A spacer selected from a linear portion having a chain length of 3-6 atoms connected to a selected point of attachment selected from the group consisting of: a heterocyclic ring having 5-8 adjacent members; R to form _XIV-9 And R _XIV-13 Independently selected from the group consisting of spacers selected from linear moieties having 2-5 atoms in chain length linked to a point of attachment selected from the group consisting of:
R _XIV-4 , R _XIV-5 , R _XIV-6 , R _XIV-7 , R _XIV-8 , R _XIV-9 , R _XIV-10 , R _XIV-11 , R _XIV-12 And R _XIV-13 Perhaloaryloxy, alkanoylalkyl, alkanoylalkoxy, alkanoyloxy, N-aryl-N-alkylamino, heterocyclicalkoxy, heterocyclicthio, hydroxyalkoxy, carboxyamidoalkoxy, alkoxycarbonylalkoxy, alkoxycarbonylalkenyloxy , Aralkanoylalkoxy, aralkenoyl, N-alkylcarboxyamide, N-haloalkylcarboxyamide, N-cycloalkylcarboxyamide, N-arylcarboxyamidealkoxy, cycloalkylcarbonyl, cyanoalkoxy, heterocyclic carbonyl, hydride, carboxy, Heteroaralkylthio, heteroaralkoxy, cycloalkylamino, acylalkyl, acylalkoxy, aroylalkoxy, heterocyclic Oxy, aralkylaryl, aralkyl, aralkenyl, aralkynyl, heterocycle, perhaloaralkyl, aralkylsulfonyl, aralkylsulfonylalkyl, aralkylsulfinyl, aralkylsulfinylalkyl, halocycloalkyl, halocycloalkenyl, cycloalkylsulfinyl, cycloalkylsulfinylalkyl, cyclo Alkylsulfonyl, cycloalkylsulfonylalkyl, heteroarylamino, N-heteroarylamino-N-alkylamino, heteroarylaminoalkyl, haloalkylthio, alkanoyloxy, alkoxy, alkoxyalkyl, haloalkoxylalkyl, heteroaralkoxy, cycloalkoxy , Cycloalkenyloxy, cycloalkoxyalkyl, cycloalkylal Xy, cycloalkenyloxyalkyl, cycloalkylenedioxy, halocycloalkoxy, halocycloalkoxyalkyl, halocycloalkenyloxy, halocycloalkenyloxyalkyl, hydroxy, amino, thio, nitro, lower alkylamino, alkylthio, alkylthioalkyl, aryl Amino, aralkylamino, arylthio, arylthioalkyl, heteroaralkoxyalkyl, alkylsulfinyl, alkylsulfinylalkyl, arylsulfinylalkyl, arylsulfonylalkyl, heteroarylsulfinylalkyl, heteroarylsulfonylalkyl, alkylsulfonyl, alkylsulfonylalkyl, haloalkyl Sulfinylalkyl, haloalkylsulfonylalkyl, al Killsulfonamide, alkylaminosulfonyl, amidosulfonyl, monoalkyl, amidosulfonyl, dialkylamidosulfonyl, monoarylamidosulfonyl, arylsulfonamide, diarylamidosulfonyl, monoalkylmonoarylamidosulfonyl, arylsulfinyl, arylsulfonyl, heteroarylthio , Heteroarylsulfinyl, heteroarylsulfonyl, heterocyclic sulfonyl, heterocyclic thio, alkanoyl, alkenoyl, aroyl, heteroaroyl, aralkanoyl, heteroaralkanoyl, haloalkanoyl, alkyl, alkenyl, alkynyl, alkenyloxy, alkenyloxyalkyl, Alkylenedioxy, haloalkylenedioxy, cycloalkyl, cycloalkyla Canoyl, cycloalkenyl, lower cycloalkylalkyl, lower cycloalkenylalkyl, halogen, haloalkyl; haloalkenyl, haloalkoxy, hydroxyhaloalkyl, hydroxyaralkyl, hydroxyalkyl, hydroxyheteroaralkyl, haloalkoxyalkyl, aryl, heteroaralkynyl, aryl Oxy, aralkoxy, aryloxyalkyl, saturated heterocycle, partially saturated heterocycle, heteroaryl, heteroaryloxy, heteroaryloxyalkyl, arylalkenyl, heteroarylalkenyl, carboxyalkyl, carboalkoxy, alkoxycarboxyamide, Alkylamidocarbonylamide, arylamidocarbonylamide, carboalkoxyalkyl, carboal Independently selected from the group consisting of xylalkenyl, carboaralkoxy, carboxyamide, carboxyamidoalkyl, cyano, carbohaloalkoxy, phosphono, phosphonoalkyl, diaralkoxyphosphono, and diaralkoxyphosphonoalkyl; Provided that 1 to 5 non-hydrido ring substituents R _XIV-4 , R _XIV-5 , R _XIV-6 , R _XIV-7 , And R _XIV-8 And 1 to 5 non-hydrido ring substituents R _XIV-9 , R _XIV-10 , R _XIV-11 , R _XIV-12 , And R _XIV-13 As well as R _XIV-4 , R _XIV-5 , R _XIV-6 , R _XIV-7 , R _XIV-8 , R _XIV-9 , R _XIV-10 , R _XIV-11 , R _XIV-12 , And R _XIV-13 Are each independently selected to maintain the tetravalent nature of carbon, the trivalent nature of nitrogen, the divalent nature of sulfur and the divalent nature of oxygen;
R _XIV-4 And R _XIV-5 , R _XIV-5 And R _XIV-6 , R _XIV-6 And R _XIV-7 , R _XIV-7 And R _XIV-8 , R _XIV-8 And R _XIV-9 , R _XIV-9 And R _XIV-10 , R _XIV-10 And R _XIV-11 , R _XIV-11 And R _XIV-12 , R _XIV-12 And R _XIV-13 Are independently selected to form a spacer pair, where the spacer pair together is a cycloalkenyl ring having 5-8 neighbors, partially saturated having 5-8 neighbors. 3 to 6 connecting the attachment points of one member of the spacer pair to form a ring selected from the group consisting of a heterocyclic ring, a heteroaryl ring having 5 to 6 adjacent members, and an aryl Forms a linear part with adjacent atoms, provided that R _XIV-4 And R _XIV-5 , R _XIV-5 And R _XIV-6 , R _XIV-6 And R _XIV-7 And R _XIV-7 And R _XIV-8 Only one of the group of spacer pairs used at the same time, as well as R _XIV-9 And R _XIV-10 , R _XIV-10 And R _XIV-11 , R _XIV-11 And R _XIV-12 And R _XIV-12 And R _XIV-13 Only one of the group of spacer pairs is used simultaneously;
R _XIV-4 And R _XIV-9 , R _XIV-4 And R _XIV-13 , R _XIV-8 And R _XIV-9 And R _XIV-8 And R _XIV-13 Are independently selected to form a spacer pair, wherein the spacer pair together form a linear portion, wherein the linear portion is a partial having 5-8 neighbors. Form a ring selected from the group consisting of a saturated heterocyclic ring and a heteroaryl ring having 5-6 adjacent members, provided that the spacer pair R _XIV-4 And R _XIV-9 , R _XIV-4 And R _XIV-13 , R _XIV-8 And R _XIV-9 And R _XIV-8 And R _XIV-13 Only one selected from the group consisting of is used simultaneously. ].

  Compounds of formula XIV are disclosed in WO 00/18721, the entire disclosure of which is hereby incorporated by reference.

In a preferred embodiment, the CETP inhibitor is selected from the following compounds of formula XIV:
3-[[3- (3-trifluoromethoxyphenoxy) phenyl] [[3- (1,1,2,2-tetrafluoroethoxy) -phenyl] methyl] amino] -1,1,1-trifluoro- 2-propanol;
3-[[3- (3-Isopropylphenoxy) phenyl] [[3- (1,1,2,2-tetrafluoroethoxy) phenyl] -methyl] amino] -1,1,1-trifluoro-2- Propanol;
3-[[3- (3-Cyclopropylphenoxy) phenyl] [[3- (1,1,2,2-tetrafluoroethoxy) phenyl] -methyl] amino] -1,1,1-trifluoro-2 -Propanol;
3-[[3- (3- (2-Furyl) phenoxy) phenyl] [[3- (1,1,2,2-tetrafluoroethoxy) phenyl] -methyl] amino] 1,1,1-trifluoro -2-propanol;
3-[[3- (2,3-dichlorophenoxy) phenyl] [[3- (1,1,2,2-tetrafluoroethoxy) phenyl] -methyl] amino] -1,1,1-trifluoro- 2-propanol;
3-[[3- (4-Fluorophenoxy) phenyl] [[3- (1,1,2,2-tetrafluoroethoxy) phenyl] -methyl] amino] -1,1,1-trifluoro-2- Propanol;
3-[[3- (4-Methylylphenoxy) phenyl] [[3- (1,1,2,2-tetrafluoroethoxy) phenyl] -methyl] amino] -1,1,1-trifluoro-2 -Propanol;
3-[[3- (2-Fluoro-5-bromophenoxy) phenyl] [[3- (1,1,2,2-tetrafluoroethoxy) phenyl] -methyl] amino] -1,1,1-tri Fluoro-2-propanol;
3-[[3- (4-Chloro-3-ethylphenoxy) phenyl] [[3- (1,1,2,2-tetrafluoroethoxy) phenyl] -methyl] amino] -1,1,1-tri Fluoro-2-propanol;
3-[[3- [3- (1,1,2,2-tetrafluoroethoxy) phenoxy] phenyl] [[3- (1,1,2,2-tetrafluoro-ethoxy) phenyl] methyl] amino] -1,1,1-trifluoro-2-propanol;
3-[[3- [3- (Pentafluoroethyl) phenoxy] phenyl] [[3- (1,1,2,2-tetrafluoroethoxy) -phenyl] methyl] amino] -1,1,1-tri Fluoro-2-propanol;
3-[[3- (3,5-Dimethylphenoxy) phenyl] [[3- (1,1,2,2-tetrafluoroethoxy) phenyl] -methyl] amino] -1,1,1-trifluoro- 2-propanol;
3-[[3- (3-Ethylphenoxy) phenyl] [[3- (1,1,2,2-tetrafluoroethoxy) phenyl] -methyl] amino] -1,1,1-trifluoro-2- Propanol;
3-[[3- (3-t-Butylphenoxy) phenyl] [[3- (1,1,2,2-tetrafluoroethoxy) phenyl] -methyl] amino] 1,1,1-trifluoro-2 -Propanol;
3-[[3- (3-Methylphenoxy) phenyl] [[3- (1,1,2,2-tetrafluoroethoxy) phenyl] -methyl] amino] -1,1,1-trifluoro-2- Propanol;
3-[[3- (5,6,7,8-tetrahydro-2-naphthoxy) phenyl] [[3- (1,1,2,2-tetrafluoroethoxy) phenyl] methyl] amino] -1,1 , 1-trifluoro-2-propanol;
3-[[3- (phenoxy) phenyl] [[3- (1,1,2,2-tetrafluoroethoxy) phenyl] methyl] amino] -1,1,1-trifluoro-2-propanol;
3-[[3- [3- (N, N-dimethylamino) phenoxy] phenyl] [[3- (1,1,2,2-tetrafluoroethoxy) phenyl] methyl] amino] -1,1,1 -Trifluoro-2-propanol;
3-[[[3- (1,1,2,2-tetrafluoroethoxy) phenyl] methyl] [3-[[3- (trifluoromethoxy) -phenyl] methoxy] phenyl] amino] -1,1, 1-trifluoro-2-propanol;
3-[[[3- (1,1,2,2-Tetrafluoroethoxy) phenyl] methyl] [3-[[3- (trifluoromethyl) -phenyl] methoxy] phenyl] amino] -1,1, 1-trifluoro-2-propanol;
3-[[[3- (1,1,2,2-Tetrafluoroethoxy) phenyl] methyl] [3-[[3,5-dimethylphenyl] -methoxy] phenyl] amino] -1,1,1- Trifluoro-2-propanol;
3-[[[3- (1,1,2,2-tetrafluoroethoxy) phenyl] methyl] [3-[[3- (trifluoromethylthio) -phenyl] methoxy] phenyl] amino] -1,1, -Trifluoro-2-propanol;
3-[[[3- (1,1,2,2-Tetrafluoroethoxy) phenyl] methyl] [3-[[3,5-difluorophenyl] -methoxy] phenyl] amino] -1,1,1- Trifluoro-2-propanol;
3-[[[3- (1,1,2,2-tetrafluoroethoxy) phenyl] methyl] [3- [cyclohexylmethoxy] -phenyl] amino] -1,1,1-trifluoro-2-propanol;
3-[[3- (2-Difluoromethoxy-4-pyridyloxy) phenyl] [[3- (1,1,2,2-tetrafluoroethoxy) -phenyl] methyl] amino] -1,1,1- Trifluoro-2-propanol;
3-[[3- (2-Trifluoromethyl-4-pyridyloxy) phenyl] [[3- (1,1,2,2-tetrafluoroethoxy) -phenyl] methyl] amino] -1,1,1 -Trifluoro-2-propanol;
3-[[3- (3-Difluoromethoxyphenoxy) phenyl] [[3- (1,1,2,2-tetrafluoroethoxy) -phenyl] methyl] amino] -1,1,1-trifluoro-2 -Propanol;
3-[[[3- (3-Trifluoromethylthio) phenoxy] phenyl] [[3- (1,1,2,2-tetrafluoroethoxy) -phenyl] methyl] amino] -1,1,1-tri Fluoro-2-propanol;
3-[[3- (4-Chloro-3-trifluoromethylphenoxy) phenyl] [[3- (1,1,2,2-tetrafluoroethoxy) -phenyl] methyl] amino] -1,1,1 , -Trifluoro-2-propanol;
3-[[3- (3-trifluoromethoxyphenoxy) phenyl] [[3- (pentafluoroethylmethyl] amino] -1,1,1-trifluoro-2-propanol;
3-[[3- (3-isopropylphenoxy) phenyl] [[3- (pentafluoroethyl) phenyl] methyl] -amino] -1,1,1-trifluoro-2-propanol;
3-[[3- (3-cyclopropylphenoxy) phenyl] [[3- (pentafluoroethyl) phenyl] methyl] -amino] -1,1,1-trifluoro-2-propanol;
3-[[3- (3- (2-furyl) phenoxy) phenyl] [[3- (pentafluoroethyl) phenyl] methyl] -amino] -1,1,1-trifluoro-2-propanol;
3-[[3- (2,3-dichlorophenoxy) phenyl] [[3- (pentafluoroethyl) phenyl] methyl] -amino] -1,1,1-trifluoro-2-propanol;
3-[[3- (4-fluorophenoxy) phenyl] [[3- (pentafluoroethyl) phenyl] methyl] -amino] -1,1,1-trifluoro-2-propanol;
3-[[3- (4-methylphenoxy) phenyl] [[3- (pentafluoroethyl) phenyl] methyl] amino] -1,1,1-trifluoro-2-propanol;
3-[[3- (2-fluoro-5-bromophenoxy) phenyl] [[3- (pentafluoroethyl) phenyl] methyl] -amino] -1,1,1-trifluoro-2-propanol;
3-[[3- (4-chloro-3-ethylphenoxy) phenyl] [[3- (pentafluoroethyl) phenyl] methyl] -amino] -1,1,1-trifluoro-2-propanol;
3-[[3- [3- (1,1,2,2-Tetrafluoroethoxy) phenoxy] phenyl] [[3- (pentafluoroethyl) -phenyl] methyl] amino] -1,1,1-tri Fluoro-2-propanol;
3-[[3- [3- (pentafluoroethyl) phenoxy] phenyl] [[3- (pentafluoroethyl) phenyl] -methyl] amino] -1,1,1-trifluoro-2-propanol;
3-[[3- (3,5-dimethylphenoxy) phenyl] [[3- (pentafluoroethyl) phenyl] methyl] -amino-1,1,1-trifluoro-2-propanol;
3-[[3- (3-ethylphenoxy) phenyl] [[3- (pentafluoroethyl) phenyl] methyl] amino] -1,1,1-trifluoro-2-propanol;
3-[[3- (3-t-butylphenoxy) phenyl] [[3- (pentafluoroethyl) phenyl] methyl] amino] -1,1,1-trifluoro-2-propanol;
3-[[3- (3-methylphenoxy) phenyl] [[3- (pentafluoroethyl) phenyl] methyl] amino] -1,1,1-trifluoro-2-propanol;
3-[[3- (5,6,7,8-Tetrahydro-2-naphthoxy) phenyl] [[3- (pentafluoroethyl) phenyl] -methyl] amino] -1,1,1-trifluoro-2 -Propanol;
3-[[3- (phenoxy) phenyl] [[3- (pentafluoroethyl) phenyl] methyl] amino] -1,1,1-trifluoro-2-propanol;
3-[[3- [3- (N, N-dimethylamino) phenoxy] phenyl] [[3- (pentafluoroethyl) phenyl] -methyl] amino] -1,1,1-trifluoro-2-propanol ;
3-[[[3- (Pentafluoroethyl) phenyl] methyl] [3-[[3- (trifluoromethoxy) phenyl] -methoxy] phenyl] amino] -1,1,1-trifluoro-2-propanol ;
3-[[[3- (Pentafluoroethyl) phenyl] methyl] [3-[[3- (trifluoromethyl) phenyl] -methoxy] phenyl] amino] -1,1,1-trifluoro-2-propanol ;
3-[[[3- (pentafluoroethyl) phenyl] methyl] [3-[[3,5-dimethylphenyl] methoxy] -phenyl] amino] -1,1,1-trifluoro-2-propanol;
3-[[[3- (Pentafluoroethyl) phenyl] methyl] [3-[[3- (trifluoromethylthio) phenyl] -methoxy] phenyl] amino] -1,1,1-trifluoro-2-propanol ;
3-[[[3- (pentafluoroethyl) phenyl] methyl] [3-[[3,5-difluorophenyl] methoxy] -phenyl] amino] -1,1,1-trifluoro-2-propanol;
3-[[[3- (pentafluoroethyl) phenyl] methyl] [3- [3- [cyclohexylmethoxy] phenyl] -amino] -1,1,1-trifluoro-2-propanol;
3-[[3- (2-difluoromethoxy-4-pyridyloxy) phenyl] [[3- (pentafluoroethyl) phenyl] -methyl] amino] -1,1,1-trifluoro-2-propanol;
3-[[3- (2-trifluoromethyl-4-pyridyloxy) phenyl] [[3- (pentafluoroethyl) phenyl] -methyl] amino] -1,1,1-trifluoro-2-propanol;
3-[[3- (3-difluoromethoxyphenoxy) phenyl] [[3- (pentafluoroethyl) phenyl] -methyl] amino] -1,1,1-trifluoro-2-propanol;
3-[[[3- (3-trifluoromethylthio) phenoxy] phenyl] [[3- (pentafluoroethyl) phenyl] -methyl] amino] -1,1,1-trifluoro-2-propanol;
3-[[3- (4-chloro-3-trifluoromethylphenoxy) phenyl] [[3- (pentafluoroethyl) -phenyl] methyl] amino] -1,1,1-trifluoro-2-propanol;
3-[[3- (3-trifluoromethoxyphenoxy) phenyl] [[3- (heptafluoropropyl) phenyl] -methyl] amino] -1,1,1-trifluoro-2-propanol;
3-[[3- (3-isopropylphenoxy) phenyl] [[3- (heptafluoropropyl) phenyl] methyl] -amino] -1,1,1-trifluoro-2-propanol;
3-[[3- (3-cyclopropylphenoxy) phenyl] [[3- (heptafluoropropyl) phenyl] methyl] -amino] -1,1,1-trifluoro-2-propanol;
3-[[3- (3- (2-furyl) phenoxy) phenyl] [[3- (heptafluoropropyl) phenyl] methyl] -amino] -1,1,1-trifluoro-2-propanol;
3-[[3- (2,3-dichlorophenoxy) phenyl] [[3- (heptafluoropropyl) phenyl] methyl] -amino] -1,1,1-trifluoro-2-propanol;
3-[[3- (4-fluorophenoxy) phenyl] [[3- (heptafluoropropyl) phenyl] methyl] -amino] -1,1,1-trifluoro-2-propanol;
3-[[3- (4-methylphenoxy) phenyl] [[3- (heptafluoropropyl) phenyl] methyl] -amino] -1,1,1-trifluoro-2-propanol;
3-[[3- (2-fluoro-5-bromophenoxy) phenyl] [[3- (heptafluoropropyl) phenyl] -methyl] amino] -1,1,1-trifluoro-2-propanol;
3-[[3- (4-chloro-3-ethylphenoxy) phenyl] [[3- (heptafluoropropyl) phenyl] methyl] -amino] -1,1,1-trifluoro-2-propanol;
3-[[3- [3- (1,1,2,2-Tetrafluoroethoxy) phenoxy] phenyl] [[3- (heptafluoropropyl) -phenyl] methyl] amino] -1,1,1-tri Fluoro-2-propanol;
3-[[3- [3- (pentafluoroethyl) phenoxy] phenyl] [[3- (heptafluoropropyl) phenyl] -methyl] amino] -1,1,1-trifluoro-2-propanol;
3-[[3- (3,5-dimethylphenoxy) phenyl] [[3- (heptafluoropropyl) phenyl] methyl] -amino] -1,1,1-trifluoro-2-propanol;
3-[[3- (3-ethylphenoxy) phenyl] [[3- (heptafluoropropyl) phenyl] methyl] amino] -1,1,1-trifluoro-2-propanol;
3-[[3- (3-t-butylphenoxy) phenyl] [[3- (heptafluoropropyl) phenyl] methyl] amino] -1,1,1-trifluoro-2-propanol;
3-[[3- (3-methylphenoxy) phenyl] [[3- (heptafluoropropyl) phenyl] methyl] amino] -1,1,1-trifluoro-2-propanol;
3-[[3- (5,6,7,8-Tetrahydro-2-naphthoxy) phenyl] [[3- (heptafluoropropyl) phenyl] -methyl] amino] -1,1,1-trifluoro-2 -Propanol;
3-[[3- (phenoxy) phenyl] [[3- (heptafluoropropyl) phenyl] methyl] amino] -1,1,1-trifluoro-2-propanol;
3-[[3- [3- (N, N-ditylamino) phenoxy] phenyl] [[3- (heptafluoropropyl) phenyl] -methyl] amino] -1,1,1-trifluoro-2-propanol;
3-[[[3- (heptafluoropropyl) phenyl] methyl] 3-[[3- (trifluoromethoxy) phenyl] -methoxy] phenyl] amino] -1,1,1-trifluoro-2-propanol;
3-[[[3- (Heptafluoropropyl) phenyl] methyl] [3-[[3- (trifluoromethyl) phenyl] -methoxy] phenyl] amino] -1,1,1-trifluoro-2-propanol ;
3-[[[3- (heptafluoropropyl) phenyl] methyl] [3-[[3,5-ditylphenyl] methoxy] -phenyl] amino] -1,1,1-trifluoro-2-propanol;
3-[[[3- (Heptafluoropropyl) phenyl] methyl] [3-[[3- (trifluoromethylthio) phenyl] -methoxy] phenyl] amino] -1,1,1-trifluoro-2-propanol ;
3-[[[3- (heptafluoropropyl) phenyl] methyl] [3-[[3,5-difluorophenyl] methoxy] -phenyl] amino] -1,1,1-trifluoro-2-propanol;
3-[[[3- (heptafluoropropyl) phenyl] methyl] [3- [cyclohexylmethoxy] phenyl] -amino] -1,1,1-trifluoro-2-propanol;
3-[[3- (2-difluoromethoxy-4-pyridyloxy) phenyl] [[3- (heptafluoropropyl) phenyl] -methyl] amino] -1,1,1-trifluoro-2-propanol;
3-[[3- (2-trifluoromethyl-4-pyridyloxy) phenyl] [[3- (heptafluoropropyl) phenyl] -methyl] amino] -1,1,1-trifluoro-2-propanol;
3-[[3- (3-difluoromethoxyphenoxy) phenyl] [[3- (heptafluoropropyl) phenyl] -methyl] amino] -1,1,1-trifluoro-2-propanol;
3-[[[3- (3-trifluoromethylthio) phenoxy] phenyl] [[3- (heptafluoropropyl) phenyl] -methyl] amino] -1,1,1-trifluoro-2-propanol;
3-[[3- (4-Chloro-3-trifluoromethylphenoxy) phenyl] [[3- (heptafluoropropyl) -phenyl] -methyl] amino] -1,1,1-trifluoro-2-propanol ;
3-[[3- (3-trifluoromethoxyphenoxy) phenyl] [[2-fluoro-5- (trifluoromethyl) -phenyl] -methyl] amino] -1,1,1-trifluoro-2-propanol ;
3-[(3- (3-isopropylphenoxy) phenyl] [[2-fluoro-5- (trifluoromethyl) phenyl] -methyl] amino] -1,1,1-trifluoro-2-propanol;
3-[[3- (3-cyclopropylphenoxy) phenyl] [[2-fluoro-5- (trifluoromethyl) phenyl] -methyl] amino] -1,1,1-trifluoro-2-propanol;
3-[[3- (3- (2-Furyl) phenoxy) phenyl] [[2-fluoro-5- (trifluoromethyl) phenyl] -methyl] amino] -1,1,1-trifluoro-2- Propanol;
3-[[3- (2,3-dichlorophenoxy) phenyl] [[2-fluoro-5- (trifluoromethyl) phenyl] -methyl] amino] -1,1,1-trifluoro-2-propanol;
3-[[3- (4-fluorophenoxy) phenyl] [[2-fluoro-5- (trifluoromethyl) phenyl] -methyl] amino] -1,1,1-trifluoro-2-propanol;
3-[[3- (4-methylphenoxy) phenyl] [[2-fluoro-5- (trifluoromethyl) phenyl] -methyl] amino] -1,1,1-trifluoro-2-propanol;
3-[[3- (2-Fluoro-5-bromophenoxy) phenyl] [[2-fluoro-5- (trifluoromethyl) -phenyl] methyl] amino] -1,1,1-trifluoro-2- Propanol;
3-[[3- (4-Chloro-3-ethylphenoxy) phenyl] [[2-fluoro-5- (trifluoromethyl) -phenyl] methyl] amino] -1,1,1-trifluoro-2- Propanol;
3-[[3- [3- (1,1,2,2-Tetrafluoroethoxy) phenoxy] phenyl] [[2-fluoro-5- (trifluoro-methyl) phenyl] methyl] amino] -1,1 , 1-trifluoro-2-propanol;
3-[[3- [3- (pentafluoroethyl) phenoxy] phenyl] [[2-fluoro-5- (trifluoromethyl) -phenyl] -methyl] amino] -1,1,1-trifluoro-2 -Propanol;
3-[[3- (3,5-dimethylphenoxy) phenyl] [[2-fluoro-5- (trifluoromethyl) phenyl] -methyl] amino] -1,1,1-trifluoro-2-propanol;
3-[[3- (3-ethylphenoxy) phenyl] [[2-fluoro-5- (trifluoromethyl) phenyl] methyl] -amino] -1,1,1-trifluoro-2-propanol;
3-[[3- (3-t-butylphenoxy) phenyl] [[2-fluoro-5- (trifluoromethyl) phenyl] methyl] -amino] -1,1,1-trifluoro-2-propanol;
3-[[3- (3-methylphenoxy) phenyl] [[2-fluoro-5- (trifluoromethyl) phenyl] methyl] -amino] -1,1,1-trifluoro-2-propanol;
3-[[3- (5,6,7,8-Tetrahydro-2-naphthoxy) phenyl] [[2-fluoro-5- (trifluoromethyl) -phenyl] methyl] amino] -1,1,1- Trifluoro-2-propanol;
3-[[3- (phenoxy) phenyl] [[2-fluoro-5- (trifluoromethyl) phenyl] methyl] amino] -1,1,1-trifluoro-2-propanol;
3-[[3- [3- (N, N-dimethylamino) phenoxy] phenyl] [[2-fluoro-5- (trifluoromethyl) -phenyl] methyl] amino] -1,1,1-trifluoro -2-propanol;
3-[[[2-Fluoro-5- (trifluoromethyl) phenyl] methyl] [3-[[3- (trifluoromethoxy) -phenyl] methoxy] phenyl] amino] -1,1,1-trifluoro -2-propanol;
3-[[[2-Fluoro-5- (trifluoromethyl) phenyl] methyl] [3-[[3- (trifluoromethyl) -phenyl] methoxy] phenyl] amino] -1,1,1-trifluoro -2-propanol;
3-[[[2-Fluoro-5- (trifluoromethyl) phenyl] methyl] [3-[[3,5- [dimethylphenyl] -methoxy] phenyl] amino] -1,1,1-trifluoro- 2-propanol;
3-[[[2-Fluoro-5- (trifluoromethyl) phenyl] methyl] [3-[[3- (trifluoromethylthio) -phenyl] methoxy] phenyl] amino] -1,1,1-trifluoro -2-propanol;
3-[[[2-Fluoro-5- (trifluoromethyl) phenyl] methyl] [3-[[3,5-difluorophenyl] -methoxy] phenyl] amino] -1,1,1-trifluoro-2 -Propanol;
3-[[[2-Fluoro-5- (trifluoromethyl) phenyl] methyl] [3- [cyclohexylmethoxy] -phenyl] amino] -1,1,1-trifluoro-2-propanol;
3-[[3- (2-Difluoromethoxy-4-pyridyloxy) phenyl] [[2-fluoro-5- (trifluoromethyl) -phenyl] methyl] amino] -1,1,1-trifluoro-2 -Propanol;
3-[[3- (2-trifluoromethyl-4-pyridyloxy) phenyl] [[2-fluoro-5- (trifluoromethyl) -phenyl] methyl] amino] -1,1,1-trifluoro- 2-propanol;
3-[[3- (3-difluoromethoxyphenoxy) phenyl] [[2-fluoro-5- (trifluoromethyl) -phenyl] methyl] amino] -1,1,1-trifluoro-2-propanol;
3-[[[3- (3-trifluoromethylthio) phenoxy] phenyl] [[2-fluoro-5- (trifluoromethyl) -phenyl] methyl] amino] -1,1,1-trifluoro-2- Propanol;
3-[[3- (4-Chloro-3-trifluoromethylphenoxy) phenyl] [[2-fluoro-5- (trifluoromethyl) phenyl] methyl] amino] -1,1,1-trifluoro-2 -Propanol;
3-[[3- (3-trifluoromethoxyphenoxy) phenyl] [[2-fluoro-4- (trifluoromethyl) -phenyl] methyl] amino] -1,1,1-trifluoro-2-propanol;
3-[[3- (3-isopropylphenoxy) phenyl] [[2-fluoro-4- (trifluoromethyl) phenyl] -methyl] amino] -1,1,1-trifluoro-2-propanol;
3-[[3- (3-cyclopropylphenoxy) phenyl] [[2-fluoro-4- (trifluoromethyl) phenyl] -methyl] amino] -1,1,1-trifluoro-2-propanol;
3-[[3- (3- (2-Furyl) phenoxy) phenyl] [[2-fluoro-4- (trifluoromethyl) phenyl] -methyl] amino] -1,1,1-trifluoro-2- Propanol;
3-[[3- (2,3-dichlorophenoxy) phenyl] [[2-fluoro-4- (trifluoromethyl) phenyl] -methyl] amino] -1,1,1-trifluoro-2-propanol;
3-[[3- (4-fluorophenoxy) phenyl] [[2-fluoro-4- (trifluoromethyl) phenyl] -methyl [amino] -1,1,1-trifluoro-2-propanol;
3-[[3- (4-methylphenoxy) phenyl] [[2-fluoro-4- (trifluoromethyl) phenyl] -methyl] amino] -1,1,1-trifluoro-2-propanol;
3-[[3- (2-Fluoro-5-bromophenoxy) phenyl] [[2-fluoro-4- (trifluoromethyl) -phenyl] methyl] amino] -1,1,1-trifluoro-2- Propanol;
3-[[3- (4-Chloro-3-ethylphenoxy) phenyl] [[2-fluoro-4- (trifluoromethyl) -phenyl] methyl] amino] -1,1,1-trifluoro-2- Propanol;
3-[[3- [3- (1,1,2,2-tetrafluoroethoxy) phenoxy] phenyl] [[2-fluoro-4- (trifluoro-methyl) phenyl] methyl] amino] -1,1 , 1-trifluoro-2-propanol;
3-[[3- [3- (pentafluoroethyl) phenoxy] phenyl] [[2-fluoro-4- (trifluoromethyl) -phenyl] methyl] amino] -1,1,1-trifluoro-2- Propanol;
3-[[3- (3,5-dimethylphenoxy) phenyl] [[2-fluoro-4- (trifluoromethyl) phenyl] -methyl] amino] -1,1,1-trifluoro-2-propanol;
3-[[3- (3-ethylphenoxy) phenyl] [[2-fluoro-4- (trifluoromethyl) phenyl] methyl] -amino] -1,1,1-trifluoro-2-propanol;
3-[[3- (3-t-butylphenoxy) phenyl] [[2-fluoro-4- (trifluoromethyl) phenyl] methyl] -amino] -1,1,1-trifluoro-2-propanol;
3-[[3- (3-methylphenoxy) phenyl] [[2-fluoro-4- (trifluoromethyl) phenyl] methyl] -amino] -1,1,1-trifluoro-2-propanol;
3-[[3- (5,6,7,8-Tetrahydro-2-naphthoxy) phenyl] [[2-fluoro-4- (trifluoromethyl) -phenyl] methyl] amino] -1,1,1- Trifluoro-2-propanol;
3-[[3- (phenoxy) phenyl] [[2-fluoro-4- (trifluoromethyl) phenyl] methyl] amino] -1,1,1-trifluoro-2-propanol;
3-[[3- [3- (N, N-dimethylamino) phenoxy] phenyl] [[2-fluoro-4- (trifluoromethyl) -phenyl] methyl] amino] -1,1,1-trifluoro -2-propanol;
3-[[[2-Fluoro-4- (trifluoromethyl) phenyl] methyl] [3-[[3- (trifluoromethoxy) -phenyl] methoxy] phenyl] amino] -1,1,1-trifluoro -2-propanol;
3-[[[2-Fluoro-4- (trifluoromethyl) phenyl] methyl] [3-[[3- (trifluoromethyl) -phenyl] methoxy] phenyl] amino] -1,1,1-trifluoro -2-propanol;
3-[[[2-Fluoro-4- (trifluoromethyl) phenyl] methyl] [3-[[3,5-dimethylphenyl] -methoxy] phenyl] amino] -1,1,1-trifluoro-2 -Propanol;
3-[[[2-Fluoro-4- (trifluoromethyl) phenyl] methyl] [3-[[3- (trifluoromethylthio) -phenyl] methoxy] phenyl] amino] -1,1,1-trifluoro -2-propanol;
3-[[[2-Fluoro-4- (trifluoromethyl) phenyl] methyl] [3-[[3,5-difluorophenyl] -methoxy] phenyl] amino] -1,1,1-trifluoro-2 -Propanol;
3-[[[2-fluoro-4- (trifluoromethyl) phenyl] methyl] [3- [cyclohexylmethoxy] -phenyl] amino] -1,1,1-trifluoro-2-propanol;
3-[[3- (2-Difluoromethoxy-4-pyridyloxy) phenyl] [[2-fluoro-4- (trifluoromethyl) -phenyl] methyl] amino] -1,1,1-trifluoro-2 -Propanol;
3-[[3- (2-trifluoromethyl-4-pyridyloxy) phenyl] [[2-fluoro-4- (trifluoromethyl) -phenyl] methyl] amino] -1,1,1-trifluoro- 2-propanol;
3-[[3- (3-difluoromethoxyphenoxy) phenyl] [[2-fluoro-4- (trifluoromethyl) -phenyl] methyl] amino] -1,1,1-trifluoro-2-propanol;
3-[[[3- (3-trifluoromethylthio) phenoxy] phenyl] [[2-fluoro-4- (trifluoromethyl) -phenyl] methyl] amino] -1,1,1-trifluoro-2- Propanol; and
3-[[3- (4-Chloro-3-trifluoromethylphenoxy) phenyl] [[2-fluoro-4- (trifluoro-methyl) phenyl] methyl] amino] -1,1,1-trifluoro- 2-propanol.

  Another class of CETP inhibitors that find utility in the present invention is the formula XV

Consisting of substituted N-aliphatic-N-aromatic tertiary-heteroalkylamines and their pharmaceutically acceptable forms:
[ _Wherein n _XV is an integer selected from 1 to 2;
A _XV and Q _{XV are-} (CR _XV-37 R _XV-38 ) _vXV- (CR _XV-33 R _XV-34 ) _uXV -T _XV- (CR _XV-35 R _XV-36 ) _wXV -H,

Independently selected from the group consisting of
However, one of A _XV and Q _XV must be AQ-1, and one of A _XV and Q _XV is AQ-2 and -CH ₂ (CR _XV-37 R _XV-38 ) _vXV- (CR _XV-33 R _XV-34 ) _uXV -T _XV- (CR _XV-35 R _XV-36 ) must be selected from the group consisting of _wXV -H;
T _XV is selected from the group consisting of a single covalent bond, O, S, S (O), S (O) ₂ , C (R _XV-33 ) = C (R _XV-35 ), and C≡C;
vXV is an integer selected from 0 to 1, provided that when any one of R _XV-33 , R _XV-34 , R _XV-35 , and R _XV-36 is aryl or heteroaryl, vXV Is 1;
uXV and wXV are integers independently selected from 0-6;
A _XV-1 is C (R _XV-30 );
D _XV-1 , D _XV-2 , J _XV-1 , J _XV-2 and K _XV-1 are independently selected from the group consisting of C, N, O, S and a covalent bond, provided that D _{XV- 1} , only _one of D _XV-2 , J _XV-1 , J _XV-2 and K _XV-1 is a covalent bond, D _XV-1 , D _XV-2 , J _XV-1 , J _XV- Only _one of ₂ and K _XV-1 is O, only _one of D _XV-1 , D _XV-2 , J _XV-1 , J _XV-2 and K _XV-1 is S, D _XV-1 , D _XV-2 , J _XV-1 , J _XV-2, and K _XV-1 are O and S, D _XV-1 , D _XV-2 , J _XV-1 , One of J _XV-2 and K _XV-1 must be a covalent bond, and a small number of D _XV-1 , D _XV-2 , J _XV-1 , J _XV-2 and K _XV-1 1 is N;
B _XV-1 , B _XV-2 , D _XV-3 , D _XV-4 , J _XV-3 , J _XV-4 , and K _XV-2 are C, C (R _XV-30 ), N, O , S and a covalent bond, but selected from B _XV-1 , B _XV-2 , D _XV-3 , D _XV-4 , J _XV-3 , J _XV-4 , and K _XV- slightly five ₂ is a covalent _{bond, B XV-1, B XV} -2, D XV-3, D XV-4, J XV-3, J XV-4, and slightly K _XV-2 2 are O and only 2 of B _XV-1 , B _XV-2 , D _XV-3 , D _XV-4 , J _XV-3 , J _XV-4 and K _XV-2 are S _Yes , only two of B _XV-1 , B _XV-2 , D _XV-3 , D _XV-4 , J _XV-3 , J _XV-4 , and K _XV-2 are O and S at the same time, And only two of B _XV-1 , B _XV-2 , D _XV-3 , D _XV-4 , J _XV-3 , J _XV-4 , and K _XV-2 are N;
B _XV-1 and D _XV-3 , D _XV-3 and J _XV-3 , J _XV-3 and K _XV-2 , K _XV-2 and J _XV-4 , J _XV-4 and D _XV-4 , D _XV-4 and B _XV-2 are independently selected to form an endocyclic spacer pair, where the spacer pair is C (R _XV-33 ) = C (R _XV-35 ) and Selected from the group consisting of N = N, provided that AQ-2 must be a ring of at least 5 contiguous members and only two groups of the spacer pair are simultaneously C (R _XV-33 ) = C (R _XV-35 ), and only one group of the spacer pairs is such that the other spacer pair is not C (R _XV-33 ) = C (R _XV-35 ), O, N and S As long as N = N can be;
R _XV-1 is selected from the group consisting of haloalkyl and haloalkoxymethyl;
R _XV-2 is selected from the group consisting of hydride, aryl, alkyl, alkenyl, haloalkyl, haloalkoxy, haloalkoxyalkyl, perhaloaryl, perhaloaralkyl, perhaloaryloxyalkyl and heteroaryl;
R _XV-3 is selected from the group consisting of hydride, aryl, alkyl, alkenyl, haloalkyl, and haloalkoxyalkyl;
Y _XV is a covalent single bond, (CH ₂ ) _q (where q is an integer selected from 1 to 2) and (CH ₂ ) _j -O- (CH ₂ ) _k (where j and k is an integer independently selected from 0 to 1).) selected from the group consisting of;
Z _XV is a covalent single bond, (CH ₂ ) _q (where q is an integer selected from 1 to 2) and (CH ₂ ) _j -O- (CH ₂ ) _k (where j and k is an integer independently selected from 0 to 1).) selected from the group consisting of;
R _XV-4 , R _XV-8 , R _XV-9 and R _XV-13 are independently selected from the group consisting of hydride, halo, haloalkyl, and alkyl;
R _XV-30 is selected from the group consisting of hydride, alkoxy, alkoxyalkyl, halogen, haloalkyl, alkylamino, alkylthio, alkylthioalkyl, alkyl, alkenyl, haloalkoxy, and haloalkoxyalkyl, wherein R _XV-30 is Selected to maintain the tetravalent nature of carbon, the trivalent nature of nitrogen, the divalent nature of sulfur and the divalent nature of oxygen;
R _XV-30 , when bound to A _XV-1 , is selected from the group consisting of R _XV-10 , R _XV-11 , R _XV-12 , R _XV-31 , and R _XV-32 together Forming an endocyclic linear spacer linked to the A _XV-1 carbon at the point of attachment of R _XV-30 to the point of attachment of the group to be formed, wherein the intracyclic linear spacer comprises 3 to 10 adjacent members A single covalent bond and 1 to 6 to form a ring selected from cycloalkyl having 5 to 10 adjacent members, cycloalkenyl having 5 to 10 adjacent members, and heterocyclic having 5 to 10 adjacent members Selected from the group consisting of spacer moieties having adjacent atoms;
When R _XV-30 is bound to A _XV-1 , together, the substituent pairs R _XV-10 and R _XV-11 , R _XV-10 and R _XV-31 , R _XV-10 and R _{XV -32} , R _XV-10 and R _XV-12 , R _XV-11 and R _XV-31 , R _XV-11 and R _XV-32 , R _XV-11 and R _XV-12 , R _XV-31 and R _{XV To the} A _XV-1 carbon at the point of attachment of any one member of the substituent pair selected from the group consisting of _-32 , R _XV-31 and R _XV-12 , and R _XV-32 and R _XV-12 Forming a linked endocyclic branched spacer, wherein the endocyclic branched spacer comprises 3 to 10 neighboring member cycloalkyl, 5 to 10 neighboring member cycloalkenyl, and 5 to Selected to form two rings selected from the group consisting of 10 adjacent member heterocyclics;
R _XV-4 , R _XV-5 , R _XV-6 , R _XV-7 , R _XV-8 , R _XV-9 , R _XV-10 , R _XV-11 , R _XV-12 , R _XV-13 , R _XV-31 , R _XV-32 , R _XV-33 , R _XV-34 , R _XV-35 , and R _XV-36 independently represent hydride, carboxy, heteroaralkylthio, heteroaralkoxy, cyclo Alkylamino, acylalkyl, acylalkoxy, aroylalkoxy, heterocyclicoxy, aralkylaryl, aralkyl, aralkylyl, aralkynyl, heterocycle, perhaloaralkyl, aralkylsulfonyl, aralkylsulfonylalkyl, aralkylsulfinyl, aralkylsulfinylalkyl, halocyclo Alkyl, halocycloalkenyl, cycloalkylsulfinyl, cycloalkylsulfinylalkyl, cycloalkylsulfonyl, cycloalkylsulfonylalkyl, heteroaryl Mino, N-heteroarylamino-N-alkylamino, heteroarylaminoalkyl, haloalkylthio, alkanoyloxy, alkoxy, alkoxyalkyl, haloalkoxylalkyl, heteroaralkoxy, cycloalkoxy, cycloalkenyloxy, cycloalkoxyalkyl, cyclo Alkylalkoxy, cycloalkenyloxyalkyl, cycloalkylenedioxy, halocycloalkoxy, halocycloalkoxyalkyl, halocycloalkenyloxy, halocycloalkenyloxyalkyl, hydroxy, amino, thio, nitro, lower alkylamino, alkylthio, alkylthioalkyl, Arylamino, aralkylamino, arylthio, arylthioalkyl, heteroaralkoxyalkyl, alkylsulfini Alkylsulfinylalkyl, arylsulfinylalkyl, arylsulfonylalkyl, heteroarylsulfinylalkyl, heteroarylsulfonylalkyl, alkylsulfonyl, alkylsulfonylalkyl, haloalkylsulfinylalkyl, haloalkylsulfonylalkyl, alkylsulfonamide, alkylaminosulfonyl, amidosulfonyl, mono Alkylamidosulfonyl, dialkylamidosulfonyl, monoarylamidosulfonyl, arylsulfonamide, diarylamidosulfonyl, monoalkylmonoarylamidosulfonyl, arylsulfinyl, arylsulfonyl, heteroarylthio, heteroarylsulfinyl, heteroarylsulfonyl, heterocyclic sulfonyl , Hete Borocyclic thio, alkanoyl, alkenoyl, aroyl, heteroaroyl, aralkanoyl, heteroaralkanoyl, haloalkanoyl, alkyl, alkenyl, alkynyl, alkenyloxy, alkenyloxyalkyl, alkylenedioxy, haloalkylenedioxy, cycloalkyl, cycloalkyl Alkanoyl, cycloalkenyl, lower cycloalkylalkyl, lower cycloalkenylalkyl, halogen, haloalkyl, haloalkenyl, haloalkoxy, hydroxyhaloalkyl, hydroxyaralkyl, hydroxyalkyl, hydroxyheteroaralkyl, haloalkoxyalkyl, aryl, heteroaralkynyl, aryl Oxy, aralkoxy, aryloxyalkyl, saturated heterocycle, partially saturated heterocycle, hete Aryl, heteroaryloxy, heteroaryloxyalkyl, arylalkenyl, heteroarylalkenyl, carboxyalkyl, carboalkoxy, alkoxycarboxyamide, alkylamidocarbonylamide, alkylamidocarbonylamide, carboalkoxyalkyl, carboalkoxyalkenyl, carboalkalkoxy , Carboxyamide, carboxyamidoalkyl, cyano, carbohaloalkoxy, phosphono, phosphonoalkyl, diaralkoxyphosphono, and diaralkoxyphosphonoalkyl, provided that R _XV-4 , R _XV-5 , R _XV-6 , R _XV-7 , R _XV-8 , R _XV-9 , R _XV-10 , R _XV-11 , R _XV-12 , R _XV-13 , R _XV-31 , R _{XV-32 , R XV-33, R XV} -34, R XV-35 and R _XV-36, are each independently, tetravalent nature of carbon, trivalent nature of nitrogen Are selected to maintain the divalent nature of divalent nature and oxygen sulfur, slightly three R _XV-33 and R _XV-34 substituents are simultaneously selected from other than the group consisting of hydrido and halogen And only three of the R _XV-35 and R _XV-36 substituents are simultaneously selected from other than the group consisting of hydride and halogen;
R _XV-9 , R _XV-10 , R _XV-11 , R _XV-12 , R _XV-13 , R _XV-31 , and R _XV-32 are independently selected to be oxo, provided that B _XV-1 , B _XV-2 , D _XV-3 , D _XV-4 , J _XV-31 , J _XV-4 , and K _XV-2 are independently selected from the group consisting of C and S, and R Only two of _XV-9 , R _XV-10 , R _XV-11 , R _XV-12 , R _XV-13 , R _XV-31 , and R _XV-32 are simultaneously oxo, and R _XV-9 , R _XV-10 , R _XV-11 , R _XV-12 , R _XV-13 , R _XV-31 , and R _XV-32 are each independently a tetravalent nature of carbon, a trivalent nitrogen Selected to maintain the nature, the divalent nature of sulfur and the divalent nature of oxygen;
R _XV-4 and R _XV-5 , R _XV-5 and R _XV-6 , R _XV-6 and R _XV-7 , R _XV-7 and R _XV-8 , R _XV-9 and R _XV-10 , R _XV-10 and R _XV-11 , R _XV-11 and R _XV-31 , R _XV-31 and R _XV-32 , R _XV-31 and R _XV-12 , and R _XV-12 and R _XV-13 Are independently selected to form a spacer pair, where the spacer pair together is a cycloalkenyl ring having 5-8 adjacent members, partially saturated having 5-8 adjacent members 3 to 6 connecting the attachment points of one member of the spacer pair to form a ring selected from the group consisting of a heterocyclic ring, a heteroaryl ring having 5 to 6 adjacent members, and an aryl Forming a linear portion having adjacent atoms of R _XV-4 and R _XV-5 , R _XV-5 and R _XV-6 , R _XV-6 and R _XV-7 , R _XV-7 and R _XV Only one of the group consisting of _-8 spacer pairs is used simultaneously, and R _XV-9 and R _XV-10 , R _XV-10 and R _XV-11 , R _XV-11 and R _{XV- 31} , R _XV-31 and R _XV-32 , R _XV-31 and R _XV-12 , and only one of R _XV-12 and R _XV-13 are used simultaneously;
R _XV-9 and R _XV-11 , R _XV-9 and R _XV-12 , R _XV-9 and R _XV-13 , R _XV-9 and R _XV-31 , R _XV-9 and R _XV-32 , R _XV-10 and R _XV-12 , R _XV-10 and R _XV-13 , R _XV-10 and R _XV-31 , R _XV-10 and R _XV-32 , R _XV-11 and R _XV-12 , R _XV-11 and R _XV-13 , R _XV-11 and R _XV-32 , R _XV-12 and R _XV-31 , R _XV-13 and R _XV-32 , and R _XV-13 and R _XV-32 Are independently selected to form a spacer pair, wherein the spacers together are cycloalkyl with 3-8 neighbors, cycloalkenyl with 5-8 neighbors, 5 In order to form a ring selected from the group consisting of a saturated heterocycle having -8 adjacent members and a partially saturated heterocycle having 5-8 adjacent members, Forming a linear spacer portion selected from the group consisting of portions having three adjacent atoms, provided that only one of the group of spacer pairs is simultaneously Is use;
R _XV-37 and R _XV-38 are from hydrido, alkoxy, alkoxyalkyl, hydroxy, amino, thio, halo, haloalkyl, alkylamino, alkylthio, alkylthioalkyl, cyano, alkyl, alkenyl, haloalkoxy, and haloalkoxyalkyl Independently selected from the group consisting of ].

  Compounds of formula XV are disclosed in WO 00/18723, the entire disclosure of which is hereby incorporated by reference.

In a preferred embodiment, the CETP inhibitor is selected from compounds of formula XV:
3-[[3- (4-chloro-3-ethylphenoxy) phenyl] (cyclohexylmethyl) amino] -1,1,1-trifluoro-2-propanol;
3-[[3- (4-chloro-3-ethylphenoxy) phenyl] (cyclopentylmethyl) amino] -1,1,1-trifluoro-2-propanol;
3-[[3- (4-Chloro-3-ethylphenoxy) phenyl] (cyclopropylmethyl) amino] -1,1,1-trifluoro-2-propanol;
3-[[3- (4-chloro-3-ethylphenoxy) phenyl] [(3-trifluoromethyl) cyclohexyl-methyl] amino] -1,1,1-trifluoro-2-propanol;
3-[[3- (4-chloro-3-ethylphenoxy) phenyl] [(3-pentafluoroethyl) cyclohexyl-methyl] amino] -1,1,1-trifluoro-2-propanol;
3-[[3- (4-chloro-3-ethylphenoxy) phenyl] [(3-trifluoromethoxy) cyclohexyl-methyl] amino] -1,1,1-trifluoro-2-propanol;
3-[[3- (4-Chloro-3-ethylphenoxy) phenyl] [[3- (1,1,2,2-tetrafluoroethoxy) cyclohexylmethyl] amino] -1,1,1-trifluoro- 2-propanol;
3-[[3- (3-trifluoromethoxyphenoxy) phenyl] (cyclohexylmethyl) amino] -1,1,1-trifluoro-2-propanol;
3-[[3- (3-trifluoromethoxyphenoxy) phenyl] (cyclopentylmethyl) amino] -1,1,1-trifluoro-2-propanol;
3-[[3- (3-trifluoromethoxyphenoxy) phenyl] (cyclopropylmethyl) amino] -1,1,1-trifluoro-2-propanol;
3-[[3- (3-trifluoromethoxyphenoxy) phenyl] [(3-trifluoromethyl) cyclohexyl-methyl] amino] -1,1,1-trifluoro-2-propanol;
3-[[3- (3-trifluoromethoxyphenoxy) phenyl]] (3-pentafluoroethyl) cyclohexyl-methyl] amino] -1,1,1-trifluoro-2-propanol;
3-[[3- (3-trifluoromethoxyphenoxy) phenyl] [(3-trifluoromethoxy) cyclohexyl-methyl] amino] -1,1,1-trifluoro-2-propanol;
3-[[3- (3-trifluoromethoxyphenoxy) phenyl] [[3- (1,1,2,2-tetrafluoroethoxy) cyclohexyl-methyl] amino] -1,1,1-trifluoro-2 -Propanol;
3-[[3- (3-Isopropylphenoxy) phenyl] (cyclohexylmethyl] amino] -1,1,1-trifluoro-2-propanol;
3-[[3- (3-Isopropylphenoxy) phenyl] (cyclopentylmethyl] amino] -1,1,1-trifluoro-2-propanol;
3-[[3- (3-Isopropylphenoxy) phenyl] (cyclopropylmethyl) amino] -1,1,1-trifluoro-2-propanol;
3-[[3- (3-Isopropylphenoxy) phenyl] [(3-trifluoromethyl) cyclohexyl-methyl] amino] -1,1,1-trifluoro-2-propanol;
3-[[3- (3-Isopropylphenoxy) phenyl] [(3-pentafluoroethyl) cyclohexyl-methyl] amino] -1,1,1-trifluoro-2-propanol;
3-[[3- (3-Isopropylphenoxy) phenyl] [(3-trifluoromethoxy) cyclohexyl-methyl] amino] -1,1,1-trifluoro-2-propanol;
3-[[3- (3-isopropylphenoxy) phenyl] [3- (1,1,2,2-tetrafluoroethoxy) cyclohexyl-methyl] amino] -1,1,1-trifluoro-2-propanol;
3-[[3- (2,3-dichlorophenoxy) phenyl] (cyclohexylmethyl) amino] -1,1,1-trifluoro-2-propanol;
3-[[3- (2,3-dichlorophenoxy) phenyl] (cyclopentylmethyl) amino] -1,1,1-trifluoro-2-propanol;
3-[[3- (2,3-dichlorophenoxy) phenyl] (cyclopropylmethyl) amino] -1,1,1-trifluoro-2-propanol;
3-[[3- (2,3-dichlorophenoxy) phenyl] [(3-trifluoromethyl) cyclohexyl-methyl] amino] -1,1,1-trifluoro-2-propanol;
3-[[3- (2,3-dichlorophenoxy) phenyl] [(3-pentafluoroethyl) cyclohexyl-methyl] amino] -1,1,1-trifluoro-2-propanol;
3-[[3- (2,3-dichlorophenoxy) phenyl] [(3-trifluoromethoxy) cyclohexyl-methyl] amino] -1,1,1-trifluoro-2-propanol;
3-[[3- (2,3-Dichlorophenoxy) phenyl] [3- (1,1,2,2-tetrafluoroethoxy) cyclohexyl-methyl] amino] -1,1,1-trifluoro-2- Propanol;
3-[[3- (4-fluorophenoxy) phenyl] (cyclohexylmethyl) amino] -1,1,1-trifluoro-2-propanol;
3-[[3- (4-fluorophenoxy) phenyl] (cyclopentylmethyl) amino] -1,1,1-trifluoro-2-propanol;
3-[[3- (4-fluorophenoxy) phenyl] (cyclopropylmethyl) amino] -1,1,1-trifluoro-2-propanol;
3-[[3- (4-fluorophenoxy) phenyl] [3-trifluoromethyl) cyclohexyl-methyl] amino] -1,1,1-trifluoro-2-propanol;
3-[[3- (4-fluorophenoxy) phenyl] [(3-penfluoroethyl) cyclohexyl-methyl] amino] -1,1,1-trifluoro-2-propanol;
3-[[3- (4-fluorophenoxy) phenyl] [(3-trifluoromethoxy) cyclohexyl-methyl] amino] -1,1,1-trifluoro-2-propanol;
3-[[3- (4-Fluorophenoxy) phenyl] [[3- (1,1,2,2-tetrafluoroethoxy) cyclohexyl-methyl] amino] -1,1,1-trifluoro-2-propanol ;
3-[[3- (3-trifluoromethoxybenzyloxy] phenyl] (cyclohexylmethyl) amino] -1,1,1-trifluoro-2-propanol;
3-[[3- (3-trifluoromethoxybenzyloxy) phenyl] (cyclopentylmethyl) amino] -1,1,1-trifluoro-2-propanol;
3-[[3- (3-trifluoromethoxybenzyloxy) phenyl] (cyclopropylmethyl] amino] -1,1,1-trifluoro-2-propanol;
3-[[3- (3-trifluoromethoxybenzyloxy) phenyl] [(3-trifluoromethyl) cyclohexyl-methyl] amino] -1,1,1-trifluoro-2-propanol;
3-[[3- (3-trifluoromethoxybenzyloxy) phenyl] [(3-pentafluoroethyl) cyclohexyl-methyl] amino] -1,1,1-trifluoro-2-propanol;
3-[[3- (3-trifluoromethoxybenzyloxy] phenyl] [(3-trifluoromethoxy) cyclohexyl-methyl] amino] -1,1,1-trifluoro-2-propanol;
3-[(3- (3-trifluoromethoxybenzyloxy) phenyl] (3- (1,1,2,2-tetrafluoroethoxy) -cyclohexylmethyl] amino] -1,1,1-trifluoro-2 -Propanol;
3-[[3- (3-trifluoromethylbenzyloxy) phenyl] (cyclohexylmethyl) amino] -1,1,1-trifluoro-2-propanol;
3-[[3- (3-trifluoromethylbenzyloxy) phenyl] (cyclopentylmethyl) amino] -1,1,1-trifluoro-2-propanol;
3-[(3- (3-trifluoromethylbenzyloxy) phenyl] (cyclopropylmethyl) amino] -1,1,1-trifluoro-2-propanol;
3-[[3- (3-trifluoromethylbenzyloxy) phenyl] (3-trifluoromethyl) cyclohexyl-methyl] amino] -1,1,1-trifluoro-2-propanol;
3-[[3- (3-trifluoromethylbenzyloxy) phenyl] [(3-pentafluoroethyl) cyclohexyl-methyl] amino] -1,1,1-trifluoro-2-propanol;
3-[[3- (3-trifluoromethylbenzyloxy) phenyl] [(3-trifluoromethoxy) cyclohexyl-methyl] amino] -1,1,1-trifluoro-2-propanol;
3-[[3- (3-Trifluoromethylbenzyloxy) phenyl] [3- (1,1,2,2-tetrafluoroethoxy) cyclohexyl-methyl] amino] -1,1,1-trifluoro-2 -Propanol;
3-[[[[(3-trifluoromethyl) phenyl] methyl] (cyclohexyl) amino] -1,1,1-trifluoro-2-propanol;
3-[[[[(3-pentafluoroethyl) phenyl] methyl] (cyclohexyl) amino] -1,1,1-trifluoro-2-propanol;
3-[[[[(3-trifluoromethoxy) phenyl] methyl] (cyclohexyl) amino] -1,1,1-trifluoro-2-propanol;
3-[[[3- (1,1,2,2-tetrafluoroethoxy) phenyl] methyl] (cyclohexyl) amino] -1,1,1-trifluoro-2-propanol;
3-[[[[(3-trifluoromethyl) phenyl] methyl] (4-methylcyclohexyl) amino] -1,1,1-trifluoro-2-propanol;
3-[[[[(3-pentafluoroethyl) phenyl] methyl] (4-methylcyclohexyl) amino] -1,1,1-trifluoro-2-propanol;
3-[[[[(3-trifluoromethoxy) phenyl] methyl]-(4-methylcyclohexyl) amino] -1,1,1-trifluoro-2-propanol;
3-[[[3- (1,1,2,2-tetrafluoroethoxy) phenyl] methyl] (4-methylcyclohexyl) amino] -1,1,1-trifluoro-2-propanol;
3-[[[[(3-trifluoromethyl] phenyl] methyl] (3-trifluoromethylcyclohexyl) amino] -1,1,1-trifluoro-2-propanol;
3-[[[(3-pentafluoroethyl) phenyl] methyl] (3-trifluoromethylcyclohexyl) amino) -1,1,1-trifluoro-2-propanol;
3-[[[[(3-trifluoromethoxy) phenyl] methyl] (3-trifluoromethylcyclohexyl) amino) -1,1,1-trifluoro-2-propanol;
3-[[[3- (1,1,2,2-tetrafluoroethoxy) phenyl] methyl] (3-trifluoromethylcyclohexyl) amino] -1,1,1-trifluoro-2-propanol;
3-[[[((3-trifluoromethyl) phenyl] methyl] [3- (4-chloro-3-ethylphenoxy) cyclohexyl] amino] -1,1,1-trifluoro-2-propanol;
3-[[[(3-pentafluoroethyl) phenyl] methyl] [3- (4-chloro-3-ethylphenoxy) cyclohexyl] amino] -1,1,1-trifluoro-2-propanol;
3-[[[(3-trifluoromethoxy) phenyl] methyl] [3- (4-chloro-3-ethylphenoxy) cyclohexyl] amino] -1,1,1-trifluoro-2-propanol;
3-[[[3- (1,1,2,2-Tetrafluoroethoxy) phenyl] methyl] [3- (4-chloro-3-ethylphenoxy) -cyclohexyl] amino] -1,1,1-tri Fluoro-2-propanol;
3-[[[[(3-trifluoromethyl] phenyl] methyl] (3-phenoxycyclohexyl) amino] -1,1,1-trifluoro-2-propanol;
3-[[[[(3-pentafluoroethyl) phenyl] methyl] (3-phenoxycyclohexyl) amino] -1,1,1-trifluoro-2-propanol;
3-[[[[(3-trifluoromethoxy) phenyl] methyl] (3-phenoxycyclohexyl) amino] -1,1,1-trifluoro-2-propanol;
3-[[[3- (1,1,2,2-tetrafluoroethoxy) phenyl] methyl] (3-phenoxycyclohexyl) amino] -1,1,1-trifluoro-2-propanol;
3-[[[[(3-trifluoromethyl) phenyl] methyl (3-isopropoxycyclohexyl) amino] -1,1,1-trifluoro-2-propanol;
3-[[[[(3-pentafluoroethyl) phenyl] methyl] (3-isopropoxycyclohexyl) amino] -1,1,1-trifluoro-2-propanol;
3-[[[[(3-trifluoromethoxy) phenyl] methyl) (3-isopropoxycyclohexyl) amino] -1,1,1-trifluoro-2-propanol;
3-[[[3- (1,1,2,2-tetrafluoroethoxy) phenyl] methyl] (3-isopropoxycyclohexyl) -amino] -1,1,1-trifluoro-2-propanol;
3-[[[[(3-trifluoromethyl) phenyl] methyl] (3-cyclopentyloxycyclohexyl] amino] -1,1,1-trifluoro-2-propanol;
3-[[[[(3-pentafluoroethyl] phenyl] methyl] (3-cyclopentyloxycyclohexyl) amino] -1,1,1-trifluoro-2-propanol;
3-[[[[(3-trifluoromethoxy) phenyl] methyl] (3-cyclopentyloxycyclohexyl) amino] -1,1,1-trifluoro-2-propanol;
3-[[[3- (1,1,2,2-tetrafluoroethoxy) phenyl] methyl] (3-cyclopentyloxycyclohexyl) -amino] -1,1,1-trifluoro-2-propanol;
3-[[[(2-trifluoromethyl) pyrid-6-yl] methyl] (3-isopropoxycyclohexyl) amino] -1,1,1-trifluoro-2-propanol;
3-[[[(2-trifluoromethyl) pyrid-6-yl] methyl] (3-cyclopentyloxycyclohexyl) amino] -1,1,1-trifluoro-2-propanol;
3-[[[(2-trifluoromethyl) pyrid-6-yl] methyl] (3-phenoxycyclohexyl) amino] -1,1,1-trifluoro-2-propanol;
3-[[[(2-trifluoromethyl) pyrid-6-yl] methyl] (3-trifluoromethylcyclohexyl) amino] -1,1,1-trifluoro-2-propanol;
3-[[[(2-Trifluoromethyl) pyrid-6-yl] methyl] [3- (4-chloro-3-ethylphenoxy) cyclohexyl] amino] -1,1,1-trifluoro-2-propanol ;
3-[[[[(2-trifluoromethyl) pyrid-6-yl] methyl] [3- (1,1,2,2-tetrafluoroethoxy) cyclohexyl] amino] -1,1,1-trifluoro- 2-propanol;
3-[[[(2-trifluoromethyl) pyrid-6-yl] methyl] (3-pentafluoroethylcyclohexyl) amino] -1,1,1-trifluoro-2-propanol;
3-[[[(2-trifluoromethyl) -pyrid-6-yl] methyl] (3-trifluoromethyloxycyclohexyl) -amino] -1,1,1-trifluoro-2-propanol;
3-[[[((3-trifluoromethyl) -phenyl] methyl] [3- (4-chloro-3-ethylphenoxy) -propyl] -amino] -1,1,1-trifluoro-2-propanol;
3-[[[[(3-pentafluoroethyl) phenyl] methyl] [3- (4-chloro-3-ethylphenoxy) propyl] -amino] -1,1,1-trifluoro-2-propanol;
3-[[[[(3-trifluoromethoxy) phenyl] methyl] [3- (4-chloro-3-ethylphenoxy) propyl] -amino] -1,1,1-trifluoro-2-propanol;
3-[[[3- (1,1,2,2-Tetrafluoroethoxy) phenyl] methyl] [3- (4-chloro-3-ethylphenoxy) -propyl] amino] -1,1,1-tri Fluoro-2-propanol;
3-[[[[(3-trifluoromethyl) phenyl] methyl] [3- (4-chloro-3-ethylphenoxy) -2,2-di-fluoropropyl] amino] -1,1,1-trifluoro- 2-propanol;
3-[[[[(3-Pentafluoroethyl) phenyl] methyl] [3- (4-chloro-3-ethylphenoxy) -2,2-di-fluoropropyl] amino] -1,1,1-trifluoro- 2-propanol;
3-[[[[(3-Trifluoromethoxy) phenyl] methyl] [3- (4-chloro-3-ethylphenoxy) -2,2, -di-fluoropropyl] amino] -1,1,1-trifluoro -2-propanol;
3-[[[3- (1,1,2,2-Tetrafluoroethoxy) phenyl] methyl] [3- (4-chloro-3-ethylphenoxy) -2,2, -difluoropropyl] amino]- 1,1,1-trifluoro-2-propanol;
3-[[[[(3-trifluoromethyl) phenyl] methyl] [3- (isopropoxy) propyl] amino] -1,1,1-trifluoro-2-propanol;
3-[[[[(3-pentafluoroethyl) phenyl] methyl] [3- (isopropoxy) propyl] amino] -1,1,1-trifluoro-2-propanol;
3-[[[[(3-trifluoromethoxy) phenyl] methyl] [3- (isopropoxy) propyl] amino] -1,1,1-trifluoro-2-propanol;
3-[[[3- (1,1,2,2-tetrafluoroethoxy) phenyl] methyl]] 3- (isopropoxy) propyl] amino] -1,1,1-trifluoro-2-propanol; and
3-[[[3- (1,1,2,2-tetrafluoroethoxy) phenyl] methyl] [3- (phenoxy) propyl] amino] -1,1,1-trifluoro-2-propanol.

  Another class of CETP inhibitors that have found utility in the present invention is the formula XVI

Consisting of (R) -chiral halogenated 1-substituted amino- (n + 1) -alkanols and their pharmaceutically acceptable forms:
_Wherein n _XVI is an integer selected from 1 to 4;
X _XVI is oxy;
R _XVI-1 is selected from the group consisting of haloalkyl, haloalkenyl, haloalkoxymethyl, and haloalkenyloxymethyl, provided that R _XVI-1 is R _XVI-2 and (CHR _XVI-3 ) _n -N (A _XVI ) Q _XVI (where A _XVI is the formula XVI- (II) and Q is the formula XVI- (III)

It is. ) Has a higher Khan-Ingold-Prelog stereochemistry system ranking than both
R _XVI-16 is selected from the group consisting of hydrido, alkyl, acyl, aroyl, heteroaroyl, trialkylsilyl, and a covalent single bond and R _XVI-4 , R _XVI-8 , R _XVI-9 and R _XVI-13 Selected from the group consisting of spacers selected from the group consisting of linear spacer moieties having a chain length of 1-4 atoms linked to the point of attachment of any aromatic substituent, and 5-10 contiguous Forming a heterocyclic ring with members;
D _XVI-1 , D _XVI-2 , J _XVI-1 , J _XVI-2 and K _XVI-1 are independently selected from the group consisting of C, N, O, S and a covalent bond, provided that D _{XVI- 1} , D _XVI-2 , J _XVI-1 , J _XVI-2 and K _XVI-1 are only covalently bonded, D _XVI-1 , D _XVI-2 , J _XVI-1 , J _XVI- Only _one of ₂ and K _XVI-1 is O, only _one of D _XVI-1 , D _XVI-2 , J _XVI-1 , J _XVI-2 and K _XVI-1 is S, When D _XVI-1 , D _XVI-2 , J _XVI-1 , J _XVI-2 and K _XVI-1 are O and S, D _XVI-1 , D _XVI-2 , J _{XVI- 1} , _one of J _XVI-2 and K _XVI-1 must be covalently bonded, and only a few of D _XVI-1 , D _XVI-2 , J _XVI-1 , J _XVI-2 and K _XVI-1 One is N,
D _XVI-3 , D _XVI-4 , J _XVI-3 , J _XVI-4 and K _XVI-2 are independently selected from the group consisting of C, N, O, S and a covalent bond, provided that D _{XVI- 3} , only one of D _XVI-4 , J _XVI-3 , J _XVI-4 and K _XVI-2 is covalent bond, D _XVI-3 , D _XVI-4 , J _XVI-3 , J _XVI- Only one of ₄ and K _XVI-2 is O, only one of D _XVI-3 , D _XVI-4 , J _XVI-3 , J _XVI-4 and K _XVI-2 is S, Only _two of D _XVI-3 , D _XVI-4 , J _XVI-3 , J _XVI-4 and K _XVI-2 are O and S, D _XVI-3 , D _XVI-4 , J _XVI-3 , J _XVI-4 and K _XVI-2 are O and S, one of D _XVI-3 , D _XVI-4 , J _XVI-3 , J _XVI-4 and K _XVI-2 is Must be covalently bonded, and only _{four of} D _XVI-3 , D _XVI-4 , J _XVI-3 , J _XVI-4 and K _XVI-2 are N;
R _XVI-2 is hydrido, aryl, aralkyl, alkyl, alkenyl, alkenyloxyalkyl, haloalkyl, haloalkenyl, halocycloalkyl, haloalkoxy, haloalkoxyalkyl, haloalkenyloxyalkyl, halocycloalkoxy, halocycloalkoxyalkyl, Selected from the group consisting of perhaloaryl, perhaloaralkyl, perhaloaryloxyalkyl, heteroaryl, dicyanoalkyl, and carboalkoxycyanoalkyl, wherein R _XVI-2 is R _XVI-1 and (CHR _XVI-3 ) _n -N (A _XVI ) Q with lower Khan-Ingold-Prelog system ranking than both _XVI ;
R _XVI-3 is hydride, hydroxy, cyano, aryl, aralkyl, acyl, alkoxy, alkyl, alkenyl, alkoxyalkyl, heteroaryl, alkenyloxyalkyl, haloalkyl, haloalkenyl, haloalkoxy, haloalkoxyalkyl, haloalkenyloxyalkyl. , Monocyanoalkyl, dicyanoalkyl, carboxamide, and carboxamidoalkyl, provided that (CHR _XVI-3 ) _n -N (A _XVI ) Q _XVI is lower than R _XVI-1 Has a Gold-Prelog Stereochemistry System Ranking and a higher Khan-Ingold-Prelog Stereochemistry System Ranking than R _XVI-2 ;
Y _XVI is a covalent single bond, (C (R _XVI-14 ) ₂ ) _q (where q is an integer selected from 1 and 2), and (CH (R _XVI-14 )) _g − W _XVI- (CH (R _XVI-14 )) _p (where g and p are integers independently selected from 0 and 1);
R _XVI-14 is hydride, hydroxy, cyano, hydroxyalkyl, acyl, alkoxy, alkyl, alkenyl, alkynyl, alkoxyalkyl, haloalkyl, haloalkenyl, haloalkoxy, haloalkoxyalkyl, haloalkenyloxyalkyl, monocarboalkoxyalkyl, Selected from the group consisting of monocyanoalkyl, dicyanoalkyl, carboalkoxycyanoalkyl, carboalkoxy, carboxyamide, and carboxyamidoalkyl;
Z _XVI is a covalent single bond, (C (R _XVI-15 ) ₂ ) _q (where q is an integer selected from 1 and 2), and (CH (R _XVI-15 )) _j − W _XVI- (CH (R _XVI-15 )) _k (where j and k are integers independently selected from 0 and 1);
W _XVI is O, C (O), C (S), C (O) N (R _XVI-14 ), C (S) N (R _XVI-14 ), (R _XVI-14 ) NC (O) , (R _XVI-14 ) NC (S), S, S (O), S (O) ₂ , S (O) ₂ N (R _XVI-14 ), (R _XVI-14 ) NS (O) ₂ , And N (R _XVI-14 ), wherein R _XVI-14 is other than cyano;
R _XVI-15 is hydrido, cyano, hydroxyalkyl, acyl, alkoxy, alkyl, alkenyl, alkynyl, alkoxyalkyl, haloalkyl, haloalkenyl, haloalkoxy, haloalkoxyalkyl, haloalkenyloxyalkyl, monocarboalkoxyalkyl, monocyano Selected from the group consisting of alkyl, dicyanoalkyl, carboalkoxycyanoalkyl, carboalkoxy, carboxyamide, and carboxyamidoalkyl;
R _XVI-4 , R _XVI-5 , R _XVI-6 , R _XVI-7 , R _XVI-8 , R _XVI-9 , R _XVI-10 , R _XVI-11 , R _XVI-12 , and R _XVI-13 Is hydride, carboxy, heteroaralkylthio, heteroaralkoxy, cycloalkylamino, acylalkyl, acylalkoxy, aroylalkoxy, heterocyclicoxy, aralkylaryl, aralkyl, aralkenyl, aralkynyl, heterocycle, perhaloaralkyl, Aralkylsulfonyl, aralkylsulfonylalkyl, aralkylsulfinyl, aralkylsulfinylalkyl, halocycloalkyl, halocycloalkenyl, cycloalkylsulfinyl, cycloalkylsulfinylalkyl, cycloalkylsulfonyl, cycloalkylsulfonylalkyl, heteroarylamino, N-heteroarylamino- N-alkylamino, f Teloaralkyl, heteroarylaminoalkyl, haloalkylthio, alkanoyloxy, alkoxy, alkoxyalkyl, haloalkoxylalkyl, heteroaralkoxy, cycloalkoxy, cycloalkenyloxy, cycloalkoxyalkyl, cycloalkylalkoxy, cycloalkenyloxyalkyl, cycloalkyl Rangeoxy, halocycloalkoxy, halocycloalkoxyalkyl, halocycloalkenyloxy, halocycloalkenyloxyalkyl, hydroxy, amino, thio, nitro, lower alkylamino, alkylthio, alkylthioalkyl, arylamino, aralkylamino, arylthio, arylthio Alkyl, heteroaralkoxyalkyl, alkylsulfinyl, alkylsulfinylalkyl Arylsulfinylalkyl, arylsulfonylalkyl, heteroarylsulfinylalkyl, heteroarylsulfonylalkyl, alkylsulfonyl, alkylsulfonylalkyl, haloalkylsulfinylalkyl, haloalkylsulfonylalkyl, alkylsulfonamide, alkylaminosulfonyl, amidosulfonyl, monoalkylamidosulfonyl, Dialkyl, amidosulfonyl, monoarylamidosulfonyl, arylsulfonamide, diarylamidosulfonyl, monoalkylmonoarylamidosulfonyl, arylsulfinyl, arylsulfonyl, heteroarylthio, heteroarylsulfinyl, heteroarylsulfonyl, heterocyclic sulfonyl, heterocyclic Formula thio, alkanoyl, Lucenoyl, aroyl, heteroaroyl, aralkanoyl, heteroaralkanoyl, haloalkanoyl, alkyl, alkenyl, alkynyl, alkenyloxy, alkenyloxyalkyl, alkylenedioxy, haloalkylenedioxy, cycloalkyl, cycloalkylalkanoyl, cycloalkenyl, lower cyclo Alkylalkyl, lower cycloalkenylalkyl, halo, haloalkyl, haloalkenyl, haloalkoxy, hydroxyhaloalkyl, hydroxyaralkyl, hydroxyalkyl, hydroxyheteroaralkyl, haloalkoxyalkyl, aryl, heteroaralkynyl, aryloxy, aralkoxy, aryloxyalkyl , Saturated heterocycle, partially saturated heterocycle, heteroaryl, heteroaryloxy , Heteroaryloxyalkyl, arylalkenyl, heteroarylalkenyl, carboxyalkyl, carboalkoxy, alkoxycarboxyamide, alkylamidocarbonylamide, arylamidocarbonylamide, carboalkoxyalkyl, carboalkoxyalkenyl, carboaralkoxy, carboxyamide, carboxy Independently selected from the group consisting of amidoalkyl, cyano, carbohaloalkoxy, phosphono, phosphonoalkyl, diaralkoxyphosphono, and diaralkoxyphosphonoalkyl, provided that R _XVI-4 , R _XVI-5 , R _XVI-6 , R _XVI-7 , R _XVI-8 , R _XVI-9 , R _XVI-10 , R _XVI-11 , R _XVI-12 , and R _XVI-13 are each independently a tetravalent carbon. Selected to maintain the properties of nitrogen, trivalent nitrogen, sulfur divalent and oxygen divalent. It is;
R _XVI-4 and R _XVI-5 , R _XVI-5 and R _XVI-6 , R _XVI-6 and R _XVI-7 , R _XVI-7 and R _XVI-8 , R _XVI-9 and R _XVI-10 , R _XVI-10 and R _XVI-11 , R _XVI-11 and R _XVI-12 , and R _XVI-12 and R _XVI-13 are independently selected to form a spacer pair, where the spacer pair is Together, a cycloalkenyl ring having 5-8 adjacent members, 5-8 adjacent members, forming a straight portion having 3-6 adjacent atoms linked to the attachment point of one member of the spacer pair Forming a ring selected from the group consisting of a partially saturated heterocyclic ring having a heteroaryl ring having 5-6 adjacent members and an aryl, provided that the spacer pairs R _XVI-4 and R _{XVI- 5} , R _XVI-5 and R _XVI-6 , R _XVI-6 and R _XVI-7 , and only one of the group consisting of R _XVI-7 and R _XVI-8 are used simultaneously, and the spacer pair R _XVI-9 and R _XVI-10 , R _XVI-10 and R _XVI-11 , R _XVI-11 and R _XVI-12 And only one of the group consisting of R _XVI-12 and R _XVI-13 can be used simultaneously;
R _XVI-4 and R _XVI-9 , R _XVI-4 and R _XVI-13 , R _XVI-8 and R _XVI-9 , and R _XVI-8 and R _XVI-13 are independent to form a spacer pair Wherein the spacer pairs together form a linear portion, wherein the linear portion is a partially saturated heterocyclic ring having 5-8 adjacent members and 5-6 Forming a ring selected from the group consisting of heteroaryl rings having adjacent members, except that the spacer pairs R _XVI-4 and R _XVI-9 , R _XVI-4 and R _XVI-13 , R _XVI-8 and R _{XVI -9} and only one of the group consisting of R _XVI-8 and R _XVI-13 are used simultaneously. ].

  Compounds of formula XVI are disclosed in WO 00/18724, the entire disclosure of which is hereby incorporated by reference.

In a preferred embodiment, the CETP inhibitor is selected from the following compounds of formula XVI:
(2R) -3-[[3- (3-Trifluoromethoxyphenoxy) phenyl] [[3- (1,1,2,2-tetrafluoroethoxy) phenyl] methyl] amino] -1,1,1- Trifluoro-2-propanol;
(2R) -3-[[3- (3-Isopropylphenoxy) phenyl] [[3- (1,1,2,2-tetrafluoroethoxy) phenyl] -methyl] amino] -1,1,1-tri Fluoro-2-propanol;
(2R) -3-[[3- (3-Cyclopropylphenoxy) phenyl] [[3- (1,1,2,2-tetrafluoroethoxy) phenyl] -methyl] amino] -1,1,1- Trifluoro-2-propanol;
(2R) -3-[[3- (3- (2-Furyl) phenoxy) phenyl] [[3- (1,1,2,2-tetrafluoroethoxy) phenyl] -methyl] amino] -1,1 , 1-trifluoro-2-propanol;
(2R) -3-[[3- (2,3-Dichlorophenoxy) phenyl] [[3- (1,1,2,2-tetrafluoroethoxy) phenyl] -methyl] amino] -1,1,1 -Trifluoro-2-propanol;
(2R) -3-[[3- (4-Fluorophenoxy) phenyl] [[3- (1,1,2,2-tetrafluoroethoxy) phenyl] -methyl] amino] -1,1,1-tri Fluoro-2-propanol;
(2R) -3-[[3- (4-Methylphenoxy) phenyl] [[3- (1,1,2,2-tetrafluoroethoxy) phenyl] -methyl] amino] -1,1,1-tri Fluoro-2-propanol;
(2R) -3-[[3- (2-Fluoro-5-bromophenoxy) phenyl] [[3- (1,1,2,2-tetrafluoroethoxy) phenyl] -methyl] amino] -1,1 , 1-trifluoro-2-propanol;
(2R) -3-[[3- (4-Chloro-3-ethylphenoxy) phenyl] [[3- (1,1,2,2-tetrafluoroethoxy) phenyl] -methyl] amino] -1,1 , 1-trifluoro-2-propanol;
(2R) -3-[[3- [3- (1,1,2,2-tetrafluoroethoxy) phenoxy] phenyl] [[3- (1,1,2,2-tetrafluoro-ethoxy) phenyl] Methyl] amino] -1,1,1-trifluoro-2-propanol;
(2R) -3-[[3- [3- (pentafluoroethyl) phenoxy] phenyl] [[3- (1,1,2,2-tetrafluoroethoxy) -phenyl] methyl] amino] -1,1 , 1-trifluoro-2-propanol;
(2R) -3-[[3- (3,5-Dimethylphenoxy) phenyl] [[3- (1,1,2,2-tetrafluoroethoxy) phenyl] -methyl] amino] -1,1,1 -Trifluoro-2-propanol;
(2R) -3-[[3- (3-Ethylphenoxy) phenyl] [[3- (1,1,2,2-tetrafluoroethoxy) phenyl] -methyl] amino] -1,1,1-tri Fluoro-2-propanol;
(2R) -3-[[3- (3-t-Butylphenoxy) -phenyl] [[3- (1,1,2,2-tetrafluoroethoxy) phenyl] -methyl] amino] -1,1, 1-trifluoro-2-propanol;
(2R) -3-[[3- (3-Methylphenoxy) phenyl] [[3- (1,1,2,2-tetrafluoroethoxy) phenyl] -methyl] amino] -1,1,1-tri Fluoro-2-propanol;
(2R) -3-[[3- (5,6,7,8-Tetrahydro-2-naphthoxy) phenyl] [[3- (1,1,2,2-tetrafluoro-ethoxy) phenyl] methyl] amino ] -1,1,1-trifluoro-2-propanol;
(2R) -3-[[3- (phenoxy) phenyl] [[3- (1,1,2,2-tetrafluoroethoxy) phenyl] methyl] amino] -1,1,1-trifluoro-2- Propanol;
(2R) -3-[[3- [3- (N, N-dimethylamino) phenoxy] phenyl] [[3- (1,1,2,2-tetrafluoro-ethoxy) phenyl] methyl] amino]- 1,1,1-trifluoro-2-propanol;
(2R) -3-[[[[3- (1,1,2,2, -tetrafluoroethoxy) phenyl] methyl] [3-[[3- (trifluoromethoxy) -phenyl] methoxy] phenyl] amino] -1,1,1-trifluoro-2-propanol;
(2R) -3-[[[[3- (1,1,2,2-tetrafluoroethoxy) phenyl] methyl] [3-[[3- (trifluoro-methyl) phenyl] methoxy] phenyl] amino]- 1,1,1-trifluoro-2-propanol;
(2R) -3-[[[[3- (1,1,2,2-tetrafluoroethoxy) phenyl] methyl] [3-[[3,5-dimethylphenyl] -methoxy] phenyl] amino] -1, 1,1-trifluoro-2-propanol;
(2R) -3-[[[[3- (1,1,2,2-tetrafluoroethoxy) phenyl] methyl] [3-[[3- (trifluoromethylthio) -phenyl] methoxy] phenyl] amino]- 1,1,1-trifluoro-2-propanol;
(2R) -3-[[[[3- (1,1,2,2-tetrafluoroethoxy) phenyl] methyl] [3-[[3,5-difluorophenyl] -methoxy] phenyl] amino] -1, 1,1-trifluoro-2-propanol;
(2R) -3-[[[[3- (1,1,2,2-tetrafluoroethoxy) phenyl] methyl] [3- [cyclohexylmethoxy] -phenyl] amino] -1,1,1-trifluoro- 2-propanol;
(2R) -3-[[3- (2-Difluoromethoxy-4-pyridyloxy) phenyl] [[3- (1,1,2,2-tetrafluoroethoxy) -phenyl] methyl] amino] -1, 1,1-trifluoro-2-propanol;
(2R) -3-[[3- (2-Trifluoromethyl-4-pyridyloxy) phenyl] [[3- (1,1,2,2-tetrafluoroethoxy) -phenyl] methyl] amino] -1 1,1-trifluoro-2-propanol;
(2R) -3-[[3- (3-Difluoromethoxyphenoxy) phenyl] [[3- (1,1,2,2-tetrafluoroethoxy) -phenyl] methyl] amino] -1,1,1- Trifluoro-2-propanol;
(2R) -3-[[[[3- (3-Trifluoromethylthio) phenoxy] phenyl] [[3- (1,1,2,2-tetrafluoroethoxy) -phenyl] methyl] amino] -1,1 , 1-trifluoro-2-propanol;
(2R) -3-[[3- (4-Chloro-3-trifluoromethylphenoxy) phenyl] [[3- (1,1,2,2-tetrafluoroethoxy) -phenyl] methyl] amino] -1 1,1-trifluoro-2-propanol;
(2R) -3-[[3- (3-trifluoromethoxyphenoxy) phenyl] [[3- (pentafluoroethyl) phenyl] -methyl] amino] -1,1,1-trifluoro-2-propanol;
(2R) -3-[[3- (3-Isopropylphenoxy) phenyl] [[3- (pentafluoroethyl) phenyl] methyl] -amino] -1,1,1-trifluoro-2-propanol;
(2R) -3-[[3- (3-cyclopropylphenoxy) phenyl] [[3- (pentafluoroethyl) phenyl] methyl] -amino] -1,1,1-trifluoro-2-propanol;
(2R) -3-[[3- (3- (2-Furyl) phenoxy) phenyl] [[3- (pentafluoroethyl) phenyl] methyl] -amino] -1,1,1-trifluoro-2- Propanol;
(2R) -3-[[3- (2,3-dichlorophenoxy) phenyl] [[3- (pentafluoroethyl) phenyl] methyl] -amino] -1,1,1-trifluoro-2-propanol;
(2R) -3-[[3- (4-Fluorophenoxy) phenyl] [[3- (pentafluoroethyl) phenyl] methyl] amino] -1,1,1-trifluoro-2-propanol;
(2R) -3-[[3- (4-methylphenoxy) phenyl] [[3- (pentafluoroethyl) phenyl] methyl] amino] -1,1,1-trifluoro-2-propanol;
(2R) -3-[[3- (2-Fluoro-5-bromophenoxy) phenyl] [[3- (pentafluoroethyl) phenyl] methyl] -amino] -1,1,1-trifluoro-2- Propanol;
(2R) -3-[[3- (4-Chloro-3-ethylphenoxy) phenyl] [[3- (pentafluoroethyl) phenyl] methyl] -amino] -1,1,1-trifluoro-2- Propanol;
(2R) -3-[[3- [3- (1,1,2,2-tetrafluoroethoxy) phenoxy] phenyl] [[3- (pentafluoroethyl) -phenyl] methyl] amino] -1,1 , 1-trifluoro-2-propanol;
(2R) -3-[[3- [3- (pentafluoroethyl) phenoxy] phenyl] [[3- (pentafluoroethyl) phenyl] -methyl] amino] -1,1,1-trifluoro-2- Propanol;
(2R) -3-[[3- (3,5-dimethylphenoxy) phenyl] [[3- (pentafluoroethyl) phenyl] methyl] -amino] -1,1,1-trifluoro-2-propanol;
(2R) -3-[[3- (3-ethylphenoxy) phenyl] [[3- (pentafluoroethyl) phenyl] methyl] amino] -1,1,1-trifluoro-2-propanol;
(2R) -3-[[3- (3-t-butylphenoxy) phenyl] [[3- (pentafluoroethyl) phenyl] methyl] amino] -1,1,1-trifluoro-2-propanol;
(2R) -3-[[3- (3-methylphenoxy) phenyl] [[3- (pentafluoroethyl) phenyl] methyl] amino] -1,1,1-trifluoro-2-propanol;
(2R) -3-[[3- (5,6,7,8-Tetrahydro-2-naphthoxy) phenyl] [[3- (pentafluoroethyl) phenyl] -methyl] amino] -1,1,1- Trifluoro-2-propanol;
(2R) -3-[[3- (phenoxy) phenyl] [[3 (pentafluoroethyl) phenyl] methyl] amino] -1,1,1-trifluoro-2-propanol;
(2R) -3-[[3- [3- (N, N-dimethylamino) phenoxy] phenyl] [[3- (pentafluoroethyl) phenyl] -methyl] amino] -1,1,1-trifluoro -2-propanol;
(2R) -3-[[[[3- (Pentafluoroethyl) phenyl] methyl] [3-[[3- (trifluoromethoxy) phenyl] -methoxy] phenyl] amino] -1,1,1-trifluoro -2-propanol;
(2R) -3-[[[3- (Pentafluoroethyl) phenyl] methyl] [3-[[3- (trifluoromethyl) -phenyl] -methoxy] phenyl] amino] -1,1,1-tri Fluoro-2-propanol;
(2R) -3-[[[3- (Pentafluoroethyl) phenyl] methyl] [3-[[3,5-dimethylphenyl] methoxy] -phenyl] amino] -1,1,1-trifluoro-2 -Propanol;
(2R) -3-[[[3- (Pentafluoroethyl) phenyl] methyl] [3-[[3- (trifluoromethylthio) phenyl] -methoxy] phenyl] amino] -1,1,1-trifluoro -2-propanol;
(2R) -3-[[[3- (Pentafluoroethyl) phenyl] methyl] [3-[[3,5-difluorophenyl] methoxy] -phenyl] amino] -1,1,1-trifluoro-2 -Propanol;
(2R) -3-[[[[3- (pentafluoroethyl) phenyl] methyl] [3- [cyclohexylmethoxy] phenyl] -amino] -1,1,1-trifluoro-2-propanol;
(2R) -3-[[3- (2-Difluoromethoxy-4-pyridyloxy) phenyl] [[3- (pentafluoroethyl) phenyl] -methyl] amino] -1,1,1-trifluoro-2 -Propanol;
(2R) -3-[[3- (2-Trifluoromethyl-4-pyridyloxy) phenyl] [[3- (pentafluoroethyl) phenyl] -methyl] amino] -1,1,1-trifluoro- 2-propanol;
(2R) -3-[[3- (3-Difluoromethoxyphenoxy) phenyl] [[3- (pentafluoroethyl) -phenyl] -methyl] amino] -1,1,1-trifluoro-2-propanol;
(2R) -3-[[[[3- (3-Trifluoromethylthio) phenoxy] phenyl] [[3- (pentafluoroethyl) phenyl] -methyl] amino] -1,1,1-trifluoro-2- Propanol;
(2R) -3-[[3- (4-Chloro-3-trifluoromethylphenoxy) phenyl] [[3- (pentafluoroethyl) -phenyl] methyl] amino] -1,1,1-trifluoro- 2-propanol;
(2R) -3-[[3- (3-trifluoromethoxyphenoxy) phenyl] [[3- (heptafluoropropyl) phenyl] -methyl] amino] -1,1,1-trifluoro-2-propanol;
(2R) -3-[[3- (3-isopropylphenoxy) phenyl] [[3- (heptafluoropropyl) phenyl] methyl] -amino] -1,1,1-trifluoro-2-propanol;
(2R) -3-[[3- (3-cyclopropylphenoxy) phenyl] [[3- (heptafluoropropyl) phenyl] methyl] -amino] -1,1,1-trifluoro-2-propanol;
(2R) -3-[[3- (3- (2-Furyl) phenoxy) phenyl] [[3- (heptafluoropropyl) phenyl] methyl] -amino] -1,1,1-trifluoro-2- Propanol;
(2R) -3-[[3- (2,3-dichlorophenoxy) phenyl] [[3- (heptafluoropropyl) phenyl] methyl] -amino] -1,1,1-trifluoro-2-propanol;
(2R) -3-[[3- (4-Fluorophenoxy) phenyl] [[3- (heptafluoropropyl) phenyl] methyl] amino] -1,1,1-trifluoro-2-propanol;
(2R) -3-[[3- (4-methylphenoxy) phenyl] [[3- (heptafluoropropyl) phenyl] methyl] amino] -1,1,1, -trifluoro-2-propanol;
(2R) -3-[[3- (2-Fluoro-5-bromophenoxy) phenyl] [[3- (heptafluoropropyl) phenyl] -methyl] amino] -1,1,1-trifluoro-2- Propanol;
(2R) -3-[[3- (4-Chloro-3-ethylphenoxy) phenyl] [[3- (heptafluoropropyl) phenyl] methyl] -amino] -1,1,1-trifluoro-2- Propanol;
(2R) -3-[[3- [3- (1,1,2,2-tetrafluoroethoxy) phenoxy] phenyl] [[3- (heptafluoropropyl) -phenyl] methyl] amino] -1,1 , 1-trifluoro-2-propanol;
(2R) -3-[[3- [3- (pentafluoroethyl) phenoxy] phenyl] [[3- (heptafluoropropyl) phenyl] -methyl] amino] -1,1,1-trifluoro-2- Propanol;
(2R) -3-[[3- (3,5-dimethylphenoxy) phenyl] [[3- (heptafluoropropyl) phenyl] methyl] -amino] -1,1,1-trifluoro-2-propanol;
(2R) -3-[[3- (3-ethylphenoxy) phenyl] [[3- (heptafluoropropyl) phenyl] methyl] amino] -1,1,1-trifluoro-2-propanol;
(2R) -3-[[3- (3-t-butylphenoxy) phenyl] [[3- (heptafluoropropyl) phenyl] methyl] amino] -1,1,1-trifluoro-2-propanol;
(2R) -3-[[3- (3-methylphenoxy) phenyl] [[3- (heptafluoropropyl) phenyl] methyl] amino] -1,1,1-trifluoro-2-propanol;
(2R) -3-[[3- (5,6,7,8-Tetrahydro-2-naphthoxy) phenyl] [[3- (heptafluoropropyl) phenyl] -methyl] amino] -1,1,1- Trifluoro-2-propanol;
(2R) -3-[[3- (phenoxy) phenyl] [[3- (heptafluoropropyl) phenyl] methyl] amino] -1,1,1-trifluoro-2-propanol;
(2R) -3-[[3- [3- (N, N-Dimethylamino) phenoxy] phenyl] [[3- (heptafluoropropyl) phenyl] -methyl] amino] -1,1,1-trifluoro -2-propanol;
(2R) -3-[[[[3- (Heptafluoropropyl) phenyl] methyl] [3-[[3- (trifluoromethoxy) phenyl] -methoxy] phenyl] amino] -1,1,1-trifluoro -2-propanol;
(2R) -3-[[[[3- (Heptafluoropropyl) phenyl] methyl] [3-[[3- (trifluoromethyl) phenyl] -methoxy] phenyl] amino] -1,1,1-trifluoro -2-propanol;
(2R) -3-[[[[3- (Heptafluoropropyl) phenyl] methyl] [3-[[3,5-dimethylphenyl] methoxy] -phenyl] amino] -1,1,1-trifluoro-2 -Propanol;
(2R) -3-[[[[3- (Heptafluoropropyl) phenyl] methyl] [3-[[3- (trifluoromethylthio) phenyl] -methoxy] phenyl] amino] -1,1,1-trifluoro -2-propanol;
(2R) -3-[[[[3- (Heptafluoropropyl) phenyl] methyl] [3-[[3-, 5-difluorophenyl] methoxy] -phenyl] amino] -1,1,1-trifluoro- 2-propanol;
(2R) -3-[[[3- (heptafluoropropyl) phenyl] methyl] [3- [cyclohexylmethoxy] phenyl] -amino] -1,1,1-trifluoro-2-propanol;
(2R) -3-[[3- (2-Difluoromethoxy-4-pyridyloxy) phenyl] [[3- (heptafluoropropyl) phenyl] -methyl] amino] -1,1,1-trifluoro-2 -Propanol;
(2R) -3-[[3- (2-Trifluoromethyl-4-pyridyloxy) phenyl] [[3- (heptafluoropropyl) phenyl] -methyl] amino] -1,1,1-trifluoro- 2-propanol;
(2R) -3-[[3- (3-Difluoromethoxyphenoxy) phenyl] [[3- (heptafluoropropyl) phenyl] -methyl] amino] -1,1,1-trifluoro-2-propanol;
(2R) -3-[[[[3- (3-Trifluoromethylthio) phenoxy] phenyl] [[3- (heptafluoropropyl) phenyl] -methyl] amino] -1,1,1-trifluoro-2- Propanol;
(2R) -3-[[3- (4-Chloro-3-trifluoromethylphenoxy) phenyl] [[3- (heptafluoropropyl) -phenyl] methyl] amino] -1,1,1-trifluoro- 2-propanol;
(2R) -3-[[3- (3-trifluoromethoxyphenoxy) phenyl] [[2-fluoro-5- (trifluoromethyl) -phenyl] methyl] amino] -1,1,1-trifluoro- 2-propanol;
(2R) -3-[[3- (3-Isopropylphenoxy) phenyl] [[2-fluoro-5- (trifluoromethyl) phenyl] -methyl] amino] -1,1,1-trifluoro-2- Propanol;
(2R) -3-[[3- (3-Cyclopropylphenoxy) phenyl] [[2-fluoro-5- (trifluoromethyl) phenyl] -methyl] amino] -1,1,1-trifluoro-2 -Propanol;
(2R) -3-[[3- (3- (2-Furyl) phenoxy) phenyl] [[3-fluoro-5- (trifluoromethyl) phenyl] -methyl] amino] -1,1,1-tri Fluoro-2-propanol;
(2R) -3-[[3- (2,3-Dichlorophenoxy) phenyl] [[2-fluoro-5- (trifluoromethyl) phenyl] -methyl] amino] -1,1,1-trifluoro- 2-propanol;
(2R) -3-[[3- (4-Fluorophenoxy) phenyl] [[2-Fluoro-5- (trifluoromethyl) phenyl] -methyl] amino-1,1,1-trifluoro-3-propanol ;
(2R) -3-[[3- (4-Methylphenoxy) phenyl] [[2-fluoro-5- (trifluoromethyl) phenyl] -methyl] amino] -1,1,1-trifluoro-2- Propanol;
(2R) -3-[[3- (2-Fluoro-5-bromophenoxy) phenyl] [[2-fluoro-5- (trifluoromethyl) -phenyl] methyl] amino] -1,1,1-tri Fluoro-2-propanol;
(2R) -3 [[3- (4-Chloro-3-ethylphenoxy) phenyl] [[2-fluoro-5- (trifluoromethyl) -phenyl] methyl] amino] -1,1,1-trifluoro -2-propanol;
(2R) -3-[[3- [3- (1,1,2,2-tetrafluoroethoxy) phenoxy] phenyl] [[2-fluoro-5- (trifluoro-methyl) phenyl] methyl] amino] -1,1,1-trifluoro-2-propanol;
(2R) -3-[[3- [3- (pentafluoroethyl) phenoxy] phenyl] [[2-fluoro-5- (trifluoromethyl) -phenyl] methyl] amino] -1,1,1-tri Fluoro-2-propanol;
(2R) -3-[[3- (3,5-Dimethylphenoxy) phenyl] [[2-fluoro-5- (trifluoromethyl) phenyl] -methyl] amino] -1,1,1-trifluoro- 2-propanol;
(2R) -3-[[3- (3-Ethylphenoxy) phenyl] [[2-fluoro-5- (trifluoromethyl) phenyl] methyl] -amino] -1,1,1-trifluoro-2- Propanol;
(2R) -3-[[3- (3-t-Butylphenoxy) phenyl] [[2-fluoro-5- (trifluoromethyl) phenyl] methyl] -amino] -1,1,1-trifluoro- 2-propanol;
(2R) -3-[[3- (3-Methylphenoxy) phenyl] [[2-fluoro-5- (trifluoromethyl) phenyl] methyl] -amino] -1,1,1-trifluoro-2- Propanol;
(2R) -3-[[3- (5,6,7,8-Tetrahydro-2-naphthoxy) phenyl] [[2-fluoro-5- (trifluoromethyl) -phenyl] methyl] amino] -1, 1,1-trifluoro-2-propanol;
(2R) -3-[[3- (phenoxy) phenyl] [[2-fluoro-5- (trifluoromethyl) phenyl] methyl] amino] -1,1,1-trifluoro-2-propanol;
(2R) -3-[[3- [3- (N, N-dimethylamino, phenoxy] phenyl] [[2-fluoro-5- (trifluoromethyl) -phenyl] methyl] amino] -1,1, 1-trifluoro-2-propanol;
(2R) -3-[[[2-Fluoro-5- (trifluoromethyl) phenyl] methyl] [3-[[3- (trifluoromethoxy) -phenyl] methoxy] phenyl] amino] -1,1, 1-trifluoro-3-propanol;
(2R) -3-[[[2-Fluoro-5- (trifluoromethyl) phenyl] methyl] [3-[[3- (trifluoromethyl) -phenyl] methoxy] phenyl] amino] -1,1, 1-trifluoro-2-propanol;
(2R) -3-[[[2-Fluoro-5- (trifluoromethyl) phenyl] methyl] [3-[[3,5-dimethylphenyl] -methoxy] phenyl] amino] -1,1,1- Trifluoro-2-propanol;
(2R) -3-[[[2-Fluoro-5- (trifluoromethyl) phenyl] methyl] [3-[[3- (trifluoromethylthio) -phenyl] methoxy] phenyl] amino] -1,1, 1-trifluoro-2-propanol;
(2R) -3-[[[2-Fluoro-5- (trifluoromethyl) phenyl] methyl] [3-[[3,5-difluorophenyl] -methoxy] phenyl] amino] -1,1,1- Trifluoro-2-propanol;
(2R) -3-[[[2-Fluoro-5- (trifluoromethyl) phenyl] methyl] [3- [cyclohexylmethoxy] -phenyl] amino] -1,1,1-trifluoro-2-propanol;
(2R) -3-[[3- (2-Difluoromethoxy-4-pyridyloxy) phenyl] [[2-fluoro-5- (trifluoromethyl) -phenyl] methyl] amino] -1,1,1- Trifluoro-2-propanol;
(2R) -3-[[3- (2-Trifluoromethyl-4-pyridyloxy) phenyl] [[2-fluoro-5- (trifluoromethyl) -phenyl] methyl] amino] -1,1,1 -Trifluoro-2-propanol;
(2R) -3-[[3- (3-Difluoromethoxyphenoxy) phenyl] [[2-fluoro-5- (trifluoromethyl) -phenyl] methyl] amino] -1,1,1-trifluoro-2 -Propanol;
(2R) -3-[[[[3- (3-trifluoromethylthio) phenoxy] phenyl] [[2-fluoro-5- (trifluoromethyl) -phenyl] methyl] amino] -1,1,1-tri Fluoro-2-propanol;
(2R) -3-[[3- (4-Chloro-3-trifluoromethylphenoxy) phenyl] [[2-fluoro-5- (trifluoro-methyl) phenyl] methyl] amino] -1,1,1 -Trifluoro-2-propanol;
(2R) -3-[[3- (3-trifluoromethoxyphenoxy) phenyl] [[2-fluoro-4- (trifluoromethyl) -phenyl] methyl] amino] -1,1,1-trifluoro- 2-propanol;
(2R) -3-[[3- (3-Isopropylphenoxy) phenyl] [[2-fluoro-4- (trifluoromethyl) phenyl] -methyl] amino] l-1,1,1-trifluoro-2 -Propanol;
(2R) -3-[[3- (3-Cyclopropylphenoxy) phenyl] [[2-fluoro-4- (trifluoromethyl) phenyl] -methyl] amino] -1,1,1-trifluoro-2 -Propanol;
(2R) -3-[[3- (3- (2-Furyl) phenoxy) phenyl] [[2-fluoro-4- (trifluoromethyl) phenyl] -methyl] amino] -1,1,1-tri Fluoro-2-propanol;
(2R) -3-[[3- (2,3-dichlorophenoxy) phenyl] [[2-fluoro-4- (trifluoromethyl) phenyl] -methyl] amino] -1,1,1-trifluoro- 2-propanol;
(2R) -3-[[3- (4-Fluorophenoxy) phenyl] [[2-fluoro-4- (trifluoromethyl) phenyl] -methyl] amino] -1,1,1-trifluoro-2- Propanol;
(2R) -3-[[3- (4-Methylphenoxy) phenyl] [[2-fluoro-4- (trifluoromethyl) phenyl] -methyl] amino] -1,1,1-trifluoro-2- Propanol;
(2R) -3-[[3- (2-Fluoro-5-bromophenoxy) phenyl] [[2-fluoro-4- (trifluoromethyl) -phenyl] methyl] amino] -1,1,1-tri Fluoro-2-propanol;
(2R) -3-[[3- (4-Chloro-3-ethylphenoxy) phenyl] [[2-fluoro-4- (trifluoromethyl) -phenyl] methyl] amino] -1,1,1-tri Fluoro-2-propanol;
(2R) -3-[[3- [3- (1,1,2,2-tetrafluoroethoxy) phenoxy] phenyl] [[2-fluoro-4- (trifluoromethyl) phenyl] methyl] amino]- 1,1,1-trifluoro-2-propanol;
(2R) -3-[[3- [3- (pentafluoroethyl) phenoxy] phenyl] [[2-fluoro-4- (trifluoromethyl) -phenyl] methyl] amino] -1,1,1-tri Fluoro-2-propanol;
(2R) -3-[[3- (3,5-Dimethylphenoxy) phenyl] [[2-fluoro-4- (trifluoromethyl) phenyl] -methyl] amino-1,1,1-trifluoro-2 -Propanol;
(2R) -3- [3- (3-Ethylphenoxy) phenyl] [[2-fluoro-4- (trifluoromethyl) phenyl] methyl] -amino] -1,1,1-trifluoro-2-propanol ;
(2R) -3-[[3- (3-t-Butylphenoxy) phenyl] [[2-fluoro-4- (trifluoromethyl) phenyl] methyl] -amino] -1,1,1-trifluoro- 2-propanol;
(2R) -3-[[3- (3-Methylphenoxy) phenyl] [[2-fluoro-4- (trifluoromethyl) phenyl] methyl] -amino] -1,1,1-trifluoro-2- Propanol;
(2R) -3-[[3- (5,6,7,8-tetrahydro-2-naphthoxy) phenyl] [[2-fluoro-4- (trifluoromethyl) -phenyl] methyl] amino] -1, 1,1-trifluoro-2-propanol;
(2R) -3-[[3- (phenoxy) phenyl] [[2-fluoro-4- (trifluoromethyl) phenyl] methyl] amino] -1,1,1-trifluoro-2-propanol;
(2R) -3-[[3- [3- (N, N-dimethylamino) phenoxy] phenyl] [[2-fluoro-4- (trifluoromethyl) -phenyl] methyl] amino] -1,1, 1-trifluoro-2-propanol;
(2R) -3-[[[2-Fluoro-4- (trifluoromethyl) phenyl] methyl] [3-[[3- (trifluoromethoxy) phenyl] methoxy] phenyl] amino] -1,1,1 -Trifluoro-2-propanol;
(3R) -3-[[[2-Fluoro-4- (trifluoromethyl) phenyl] methyl] [3-[[3- (trifluoromethyl) phenyl] methoxy] phenyl] amino] -1,1,1 -Trifluoro-2-propanol;
(2R) -3-[[[2-Fluoro-4- (trifluoromethyl) phenyl] methyl] [3-[[3,5-dimethylphenyl] -methoxy] phenyl] amino] -1,1,1- Trifluoro-2-propanol;
(2R) -3-[[[2-Fluoro-4- (trifluoromethyl) phenyl] methyl] [3-[[3- (trifluoromethylthio) -phenyl] methoxy] phenyl] amino] -1,1, 1-trifluoro-2-propanol;
(2R) -3-[[[2-Fluoro-4- (trifluoromethyl) phenyl] methyl] [3-[[3,5-difluorophenyl] -methoxy] phenyl] amino] -1,1,1- Trifluoro-2-propanol;
(2R) -3-[[[2-Fluoro-4- (trifluoromethyl) phenyl] methyl] [3- [cyclohexylmethoxy] -phenyl] amino] -1,1,1-trifluoro-2-propanol;
(2R) -3-[[3- (2-Difluoromethoxy-4-pyridyloxy) phenyl] [[2-fluoro-4- (trifluoromethyl) -phenyl] methyl] amino] -1,1,1- Trifluoro-2-propanol;
(2R) -3-[[3- (2-Trifluoromethyl-4-pyridyloxy) phenyl] [[2-fluoro-4- (trifluoromethyl) -phenyl] methyl] amino] -1,1,1 -Trifluoro-2-propanol;
(2R) -3-[[3- (3-Difluoromethoxyphenoxy) phenyl] [[2-fluoro-4- (trifluoromethyl) -phenyl] methyl] amino] -1,1,1-trifluoro-2 -Propanol;
(2R) -3-[[[3- (3-Trifluoromethylthio) phenoxy] phenyl] [[2-fluoro-4- (trifluoromethyl) -phenyl] methyl] amino] -1,1,1-tri Fluoro-2-propanol; and
(2R) -3-[[3- (4-Chloro-3-trifluoromethylphenoxy) phenyl] [[2-fluoro-4- (trifluoromethyl) phenyl] methyl] amino] -1,1,1- Trifluoro-2-propanol.

  Another class of CETP inhibitors that have found utility in the present invention is the formula XVII

Consisting of quinolines and their pharmaceutically acceptable forms having:
Wherein A _XVII means an aryl containing 6 to 10 carbon atoms, which may be halogen, nitro, hydroxyl, trifluoromethyl, trifluoromethoxy, or a straight chain containing up to 7 carbon atoms each. Optionally substituted with up to 5 same or different substituents in the form of a chain or branched alkyl, acyl, hydroxyalkyl or alkoxy, or of the formula -NR _XVII-4 R _XVII-5 ;
(Wherein R _XVII-4 and R _XVII-5 are the same or different and mean hydrogen, phenyl, or straight-chain or branched alkyl containing up to 6 carbon atoms);
D _XVII means an aryl containing 6 to 10 carbon atoms, which is phenyl, nitro, halogen, trifluoromethyl or trifluoromethoxy, or

Optionally substituted by a radical of
(Wherein, R _XVII-6 , R _XVII-7 , R _XVII-10 independently of one another are cycloalkyl containing 3 to 6 carbon atoms, or aryl containing 6 to 10 carbon atoms, or 5- to 7-membered, optionally benzo-fused, saturated or unsaturated, mono-, bi- or tricyclic hetero, containing up to 4 heteroatoms of the set S, N and / or O Means rings, where these rings are halogen, trifluoromethyl, nitro, hydroxyl, cyano, carboxyl, trifluoromethoxy, each with up to 6 carbon atoms in the case of nitrogen-containing rings via the N function Linear or branched acyl, including, alkyl, alkylthio, alkylalkoxy, alkoxy or alkoxycarbonyl, aryl or trifluoromethyl-substituted aryl containing 6 to 10 carbon atoms each, or Or the best of O pair Three benzo optionally containing a hetero atom - fused, aromatic 5- to 7-membered heterocycle, and / or formula _{-ORX VII-11, -SR XVII-} 12, -SO 2 R XVII-13 Or optionally substituted with up to 5 same or different substituents in the form -NR _XVII-14 R _XVII-15 ;
X _VII-11 , R _XVII-12 , and R _XVII-13 , independently of one another, mean aryl containing 6 to 10 carbon atoms, which in turn is phenyl, halogen or up to 6 carbons. Substituted with up to two identical or different substituents in the form of straight or branched alkyl containing atoms,
R _XVII-14 and R _XVII-15 are the same or different and have the meanings of R _XVII-4 and R _{XVII-5 set} forth above, or
R _XVII-6 and R _XVII-7 are radicals of the formula

Means
R _XVII-8 means hydrogen or halogen, and
R _XVII-9 is hydrogen, halogen, azide, trifluoromethyl, hydroxyl, trifluoromethoxy, straight or branched alkoxy or alkyl each containing up to 6 carbon atoms, or the formula NR _XVII-16 R _XVII Means _-17 radicals;
R _XVII-16 and R _XVII-17 are the same or different and have the meanings of R _XVII-4 and R _XVII-5 above; or
R _XVII-8 and R _XVII-9 together form a radical of formula = O or = NR _XVII-18 ;
R _XVII-18 means hydrogen or straight or branched alkyl, alkoxy or acyl each containing up to 6 carbon atoms;
L _XVII means a straight or branched alkylene or alkenylene chain each containing up to 8 carbon atoms, optionally substituted by up to 2 hydroxyl groups;
T _XVII and X _XVII mean the same or different, straight or branched alkylene chain containing up to 8 carbon atoms; or
T _XVII and X _XVII mean a bond;
V _XVII means an oxygen or sulfur atom or -NR _XVII-19 ;
R _XVII-19 means hydrogen or straight-chain or branched alkyl containing up to 6 carbon atoms or phenyl. );
E _XVII means a cycloalkyl containing 3 to 8 carbon atoms, or a straight or branched alkyl containing up to 8 carbon atoms, which is a cycloalkyl containing 3 to 8 carbon atoms. Optionally substituted with alkyl, or hydroxyl, or phenyl optionally substituted with halogen or trifluoromethyl;
R _XVII-1 and R _XVII-2 are the same or different and are cycloalkyl containing 3 to 8 carbon atoms, hydrogen, nitro, halogen, trifluoromethyl, trifluoromethoxy, carboxy, hydroxy, cyano, linear or Means branched chain acyl, alkoxycarbonyl or alkoxy with up to 6 carbon atoms, or NR _XVII-20 R _XVII-21 ;
R _XVII-20 and R _XVII-21 are the same or different and mean hydrogen, phenyl, or straight-chain or branched alkyl with up to 6 carbon atoms; and / or
R _XVII-1 and / or R _XVII-2 are linear or branched alkyl with up to 6 carbon atoms, optionally substituted with halogen, trifluoromethoxy, hydroxy, or up to 4 carbons Linear or branched alkoxy with atoms, halogen, cyano, hydroxy, trifluoromethyl, trifluoromethoxy, nitro, linear or branched alkyl with up to 7 carbon atoms, acyl, hydroxyalkyl, Aryl containing 6-10 carbon atoms optionally substituted with up to 5 identical or different substituents selected from alkoxy, as well as NR _XVII-22 R _XVII-23 ;
R _XVII-22 and R _XVII-23 are the same or different and mean hydrogen, phenyl or straight-chain or branched alkyl with up to 6 carbon atoms; and / or
R _XVII-1 and R _XVII-2 together are a halogen, trifluoromethyl, hydroxy, or up to 6 optionally substituted by straight or branched alkoxy with up to 5 carbon atoms Forming a linear or branched alkene or alkane with carbon atoms;
R _XVII-3 is hydrogen, benzoyl optionally substituted by straight or branched acyl with up to 20 carbon atoms, halogen, trifluoromethyl, nitro or trifluoromethoxy, up to 8 carbon atoms And straight or branched fluoroacyl with 7 fluorine atoms, cycloalkyl with 3 to 7 carbon atoms, straight or branched with up to 8 carbon atoms optionally substituted by hydroxyl Chain alkyl, linear or branched alkoxy with up to 6 carbon atoms optionally substituted by phenyl, which in turn is halogen, nitro, trifluoromethyl, trifluoromethoxy, or phenyl Or substituted with an alkyl optionally substituted with a tetrazole-substituted phenyl and / or a group of formula —OR _XVII-24 ;
R _XVII-24 is a straight or branched acyl or benzyl with up to 4 carbon atoms. ].

  The compound of formula XVII is disclosed in WO 98/39299, the entire disclosure of which is hereby incorporated by reference.

  Another class of CETP inhibitors that have found utility in the present invention is the formula XVIII

Consisting of 4-phenyltetrahydroquinolines, their N-oxides, and their pharmaceutically acceptable forms:
_Wherein A _XVIII is optionally substituted with up to 2 identical or different substituents in the form of halogen, trifluoromethyl, or a straight or branched alkyl or alkoxy containing up to 3 carbon atoms. Means substituted phenyl;
D _XVIII is the following formula

Means;
R _XVIII-5 and R _XVIII-6 together form ═O; or
R _XVIII-5 means hydrogen and R _XVIII-6 means halogen or hydrogen; or
R _XVIII-5 and R _XVIII-6 mean hydrogen;
R _XVIII-7 and R _XVIII-8 are the same or different and have a maximum of 4 in the form of halogen, trifluoromethyl, nitro, cyano, trifluoromethoxy, —SO ₂ —CH ₃ or NR _XVIII-9 R _XVIII-10. Means phenyl, naphthyl, benzothiazolyl, quinolinyl, pyrimidyl or pyridyl, with the same or different substituents;
R _XVIII-9 and R _XVIII-10 are the same or different and represent hydrogen or straight-chain or branched alkyl of up to 3 carbon atoms;
E _XVIII means cycloalkyl of 3 to 6 carbon atoms, or straight-chain or branched alkyl of up to 8 carbon atoms;
R _XVIII-1 means hydroxy;
R _XVIII-2 means hydrogen or methyl;
R _XVIII-3 and R _XVIII-4 are the same or different and mean straight or branched alkyl of up to 3 carbon atoms;
R _XVIII-3 and R _XVIII-4 together form an alkenyl of up to 2-4 carbon atoms. ].

  The compound of formula XVIII is disclosed in WO 99/15504, the entire disclosure of which is hereby incorporated by reference.

  Another class of CETP inhibitors that find utility in the present invention is the formula XIX

And consisting of aminoethanol derivatives and their pharmaceutically acceptable forms:
[In the formula, Ar _XIX-1 means an aromatic ring group which may contain a substituent;
Ar _XIX-2 means an aromatic ring group which may contain a substituent;
R _XIX means an acyl group;
R ′ _XIX means a hydrogen atom or a hydrocarbon group that may contain substituents; and
OR " _XIX means a hydroxyl group that may be protected.]

  Compounds of formula XIX are disclosed in WO 2002/059077, the entire disclosure of which is incorporated herein by reference.

In a preferred embodiment, the CETP inhibitor is selected from the following compounds of formula XIX or salts thereof:
N-[(1RS, 2SR) -2- (4-Fluorophenyl) -2-hydroxy-1- [4- (trifluoromethyl) benzyl] ethyl] -6,7-dihydro-5H-benzo [a] cyclopentene -1-carboxamide;
4-fluoro-N-((1R, 2S) -2- (4-fluorophenyl) -2-hydroxy-1-((4- (trifluoromethyl) phenyl) methyl) ethyl) -1-naphthalenecarboxamide;
N-[(1R, 2S) -2- (4-fluorophenyl) -2-hydroxy-1- [3- (1,1,2,2-tetrafluoroethoxy) benzyl] ethyl] -6,7-dihydro -5H-benzo [a] cyclopentene-1-carboxamide;
N-[(1RS, 2SR) -2- (4-fluorophenyl) -2-hydroxy-1- [3- (1,1,2,2-tetrafluoroethoxy) benzyl] ethyl] -5,6-dihydro Naphthalene-1-carboxamide;
N-[(1RS, 2SR) -2- (4-fluorophenyl) -2-hydroxy-1- [3- (1,1,2,2-tetrafluoroethoxy) benzyl] ethyl] -6,7,8 , 9-Tetrahydro-5H-benzo [a] cycloheptene-1-carboxamide;
4-Fluoro-N-[(1R, 2S) -2- (4-fluorophenyl) -2-hydroxy-1- [3- (1,1,2,2-tetrafluoroethoxy) benzyl] ethyl] naphthalene- 1-carboxamide;
N-[(1RS, 2SR) -2- (4-fluorophenyl) -2-hydroxy-1- [3- (1,1,2,2-tetrafluoroethoxy) benzyl] ethyl] -5,6,7 , 8-tetrahydrobenzo [a] cyclooctene-1-carboxamide;
N-[(1RS, 2SR) -2- (4-Fluorophenyl) -2-hydroxy-1- (4-isopropylbenzyl) ethyl] -6,7-dihydro-5H-benzo [a] cycloheptene-1-carboxy An amide;
N-((1RS, 2SR) -2- (3-fluorophenyl) -2-hydroxy-1-((4- (trifluoromethyl) phenyl) methyl) ethyl) -6,7-dihydro-5H-benzo [ a] cycloheptene-1-carboxamide;
N-((1RS, 2SR) -2-hydroxy-2- (4-phenoxyphenyl) -1-((4- (trifluoromethyl) phenyl) methyl) ethyl) -6,7-dihydro-5H-benzo [ a] cycloheptene-1-carboxamide;
N-[(1RS, 2SR) -2- (4-chlorophenyl) -2-hydroxy-1- [3- (1,1,2,2-tetrafluoroethoxy) benzyl) ethyl) -6,7-dihydro- 5H-benzo [a] cycloheptene-1-carboxamide;
N-((1RS, 2SR) -2-hydroxy-2- (4-phenyloxy) phenyl) -1-((3-((1,1,2,2-tetrafluoroethyl) oxy) phenyl) methyl) Ethyl) -6,7-dihydro-5H-benzo [a] cycloheptene-1-carboxamide;
N-((1RS, 2SR) -2- (4-((4-chloro-3-ethylphenyl) oxy) phenyl) -2-hydroxy-1-((3-((1,1,2,2- Tetrafluoroethyl) oxy) phenyl) methyl) ethyl) -6,7-dihydro-5H-benzo [a] cycloheptene-1-carboxamide;
N- (1RS, 2SR) -2- (2-fluoropyridin-4-yl) -2-hydroxy-1-((3-((1,1,2,2-tetrafluoroethoxy) phenyl) methyl) ethyl ) -6,7-dihydro-5H-benzo [a] cycloheptene-1-carboxamide;
N-((1RS, 2RS) -2- (6-fluoropyridin-2-yl) -2-hydroxy-1-((3-((1,1,2,2-tetrafluoroethoxy) phenyl) methyl) Ethyl) -6,7-dihydro-5H-benzo [a] cycloheptene-1-carboxamide;
N-[(1RS, 2SR) -1- (4-tert-butylbenzyl) -2- (3-chlorophenyl) -2-hydroxyethyl] -5-chloro-1-naphthamide;
4-Fluoro-N-{(1RS, 2SR) -2- (4-fluorophenyl) -2-hydroxy-1-[(2,2,3,3-tetrafluoro-2,3-dihydro-1,4 -Benzodioxin-6-yl) methyl] ethyl} -1-naphthamide.

  In a preferred embodiment, the CETP inhibitor is [2R, 4S] -4-[(3,5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -2-ethyl, also known as torcetrapib. -6-Trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester. Torcetrapib is represented by the following formula.

  CETP inhibitors, particularly torcetrapib, and methods for preparing such compounds are described in U.S. Patent Nos. 6,197,786 and 6,313,142, PCT International Publication Nos. 01 / 40190A1, 02 / 088085A2, and 02 / 088069A2. The disclosures of which are incorporated herein by reference. Torcetrapib has low solubility, usually in an aqueous environment like the luminal fluid of the human GI tract. The solubility of torcetrapib in water is less than about 0.04 μg / ml. Torcetrapib is shown in the GI tract in an enhanced solubility with the aim of achieving sufficient drug concentration in the GI tract to achieve sufficient absorption into the blood to elicit the desired therapeutic effect. It must be.

<Amorphous solid dispersion of CETP inhibitor>
The CETP inhibitor and the thickening polymer are combined to form an amorphous solid dispersion. An amorphous solid dispersion means a solid material in which at least a portion of the CETP inhibitor is in an amorphous form and is dispersed in the polymer. Preferably, the CETP inhibitor that is at least the major portion in the amorphous solid dispersion is amorphous. “Amorphous” simply means that the CETP inhibitor is in a non-crystalline state. As used herein, the term “major portion” of a CETP inhibitor means that at least 60 wt% of the drug in the amorphous solid dispersion is in an amorphous form rather than a crystalline form. Preferably, the CETP inhibitor in the amorphous solid dispersion is substantially amorphous. “Substantially amorphous” as used herein means that the amount of crystalline form of CETP inhibitor does not exceed about 25 wt%. More preferably, the CETP inhibitor of the amorphous solid dispersion is “almost completely amorphous”, which means that the amount of crystalline form of the CETP inhibitor does not exceed about 10 wt%. The amount of crystalline CETP inhibitor can be measured by powder X-ray diffraction (PXRD), scanning electron microscope (SEM) analysis, differential scanning calorimetry (DSC), or any other standard quantitative measurement.

  The solid dispersion can contain about 1 to about 80 wt% CETP inhibitor, depending on the dose of CETP inhibitor and the effect of the thickening polymer. The increase in aqueous CETP inhibitor concentration and relative bioavailability is typically best at low CETP inhibitor levels, typically less than about 25 to about 40 wt%. However, due to practical limitations in dosage form size, higher CETP inhibitor levels may be preferred and often work well.

  Since the solid solution of the drug is homogeneously distributed throughout the polymer or in a combination of those states located in or between them, amorphous CETP inhibitors are relatively pure amorphous drug domains Or it can be present in an amorphous solid dispersion in the region. The amorphous solid dispersion is preferably substantially homogeneous so that the amorphous CETP inhibitor is dispersed as homogeneously as possible throughout the polymer. As used herein, “substantially homogeneous” refers to a relatively small fraction of CETP inhibitor present in a relatively pure amorphous drug domain or region within an amorphous solid dispersion, Meaning less than 20 wt% of the total amount of drug, preferably less than 10 wt%. An amorphous solid dispersion that is substantially homogeneous is generally more physically stable and has improved thickening properties and therefore improved bioavailability compared to a non-homogeneous dispersion.

Percentage of drug present in relatively pure amorphous drug domains or regions within an amorphous solid dispersion when CETP inhibitors and polymers have sufficiently far apart glass transition temperatures (greater than about 20 ° C.) Can be determined by testing the glass transition temperature (T _g ) of the amorphous solid dispersion. The T _g, as used herein, when heating the glassy material gradually, relatively quickly (e.g., within 10 to 100 seconds) characteristic temperature to undergo physical change from a glassy to rubbery in It is. T _g of amorphous materials such as polymers, drugs, or dispersions should be measured by several techniques, including by dynamic mechanical analysis (DMA), dilatometer, dielectric constant analyzer, and DSC Can do. The exact values measured by each technique vary slightly but usually settle within 10-30 ° C of each other. If the solid amorphous dispersion exhibits a single T _g, the amount of CETP inhibitor in pure amorphous drug domains or regions of an amorphous solid dispersion body is generally less than about 10 wt%, which is Ensure that the amorphous solid dispersion is substantially homogeneous. This is one is and one a T _g of the drug is a T _g of the polymer, simple physical mixture of the general pure show two different T _g in amorphous drug particles and pure amorphous polymer particles In contrast to One is T _g and one of substantially drug is of the remainder of the drug / polymer dispersion, the solid amorphous dispersion that shows two different T _g, at least a portion of the drug, a relatively pure amorphous Exists in the quality domain. The amount of CETP inhibitor present in a relatively pure amorphous drug domain or region is initially determined to determine the T _g of the amorphous solid dispersion vs. the drug loaded in that dispersion. Can be determined by preparing a calibration standard for a homogeneous dispersion. From these calibration data and the T _g of the drug / polymer dispersion, the fraction of CETP inhibitors in relatively pure amorphous drug domains or regions can be determined. Alternatively, the CETP inhibitor present in relatively pure amorphous drug domains or regions amounts, essentially consisting of a physical mixture of amorphous drug and polymer of the calibration standards and transition near the drug T _g It can be determined by comparing the magnitude of the heat capacity for. In any case, the amorphous solid dispersion is a fraction of CETP inhibitor present in a relatively pure amorphous drug domain or region within the amorphous solid dispersion, wherein the total amount of CETP inhibitor is , Less than 20 wt%, preferably less than 10 wt%, is considered substantially homogeneous.

<Acid thickened polymer>
The amorphous solid dispersion of the present invention contains a CETP inhibitor and an acidic concentrated polymer. Acid concentrated polymers suitable for use in amorphous solid dispersions are inert in the sense that they do not chemically react with CETP inhibitors in a deleterious manner. The polymer must have a solubility in water of at least 0.1 mg / mL for at least part of the pH range 1-8.

  “Acid polymer” means a polymer having a significant number of acidic moieties. In general, a significant number of acidic moieties will be greater than or equal to about 0.1 milliequivalent of acidic moieties per gram of polymer. An “acidic moiety” is any functional group that is at least partially capable of providing hydrogen cations to water when contacted or dissolved with water, and is thus sufficiently acidic to increase the hydrogen-ion concentration. Contains groups. This definition includes functional groups or “substituents” that are referred to as having a pKa of less than about 10 when the functional group is covalently attached to the polymer. Thus, the term pKa is used in its traditional form, where pKa is the negative logarithm of the ionization constant of the acid. pKa will be affected by factors such as solvent, temperature, water content, and ionic strength of the medium or base in which the acid is present. Unless otherwise noted, pKa is assumed to be measured in distilled water at 25 ° C. In general, since more acidic polymers are more useful in the present invention, the present invention is preferred for polymers with functional groups with a pKa of less than about 7, even more preferably a pKa of less than about 6. Examples of functional group types included in the foregoing description include carboxylic acid, thiocarboxylic acid, phosphoric acid, phenolic group, and sulfonic acid group. Such functional groups can form the primary structure of polymers such as polyacrylic acid, but more commonly are covalently attached to the backbone of the parent polymer and are therefore referred to as “substituents”.

  The thickened polymer is preferably “amphiphilic” in nature, meaning that the polymer has a hydrophobic portion and a hydrophilic portion. Such polymers are preferred because amphiphilic polymers tend to interact relatively strongly with drugs and can promote the formation of various types of polymer / drug assemblies in solution. A particularly preferred type of amphiphilic polymer is one that is ionizable, and the ionizable portion of such a polymer, when ionized, constitutes at least a portion of the hydrophilic portion of the polymer. For example, without intending to be bound by any particular theory, such polymer / drug assemblies are composed of a hydrophobic region of the polymer that is inward to the drug and a hydrophilic region of the polymer that is outward to the aqueous environment. May contain hydrophobic drug clusters surrounded by a thickened polymer with Alternatively, depending on the specific chemical nature of the drug, the ionized functional groups of the polymer can be associated with the ionic or polar groups of the drug, for example via ion pairs or hydrogen bonds. In the case of an ionizable polymer, the hydrophilic region of the polymer will contain ionized functional groups. In addition, the similar charge repulsion of the ionized groups of such polymers (where the polymer is ionizable) limits the size of the polymer / drug assembly from nanometer to sub-micron. Would help. Such drug / concentrated polymer assemblies in solution may closely resemble charged polymer micelle-like structures. In any case, regardless of the mechanism of action, the inventors have found that such amphiphilic polymers, in particular ionizable cellulosic polymers as listed below, have higher concentrations in aqueous use environments. It was found that it was shown to interact with the drug to maintain the drug.

  One type of acidic thickened polymer suitable for use in the present invention includes ionizable non-cellulosic polymers. Examples of polymers include: Carboxylic acid-functionalized vinyl polymers such as carboxylic acid functionalized polymethacrylates and carboxylic acid functionalized polyacrylates such as by Rohm Tech (Maiden, MA) EUDRAGIT ™ manufactured; proteins such as gelatin and albumin; and carboxylic acid functionalized starches such as starch glycolate.

  Non-cellulosic polymers that are amphiphilic are copolymers of monomers that are relatively hydrophilic and monomers that are relatively hydrophobic. Examples include acrylic acid and methacrylic acid copolymers. Examples of commercial products of such copolymers include the EUDRAGITE ™ series, which are copolymers of methacrylic acid and acrylic acid.

  A preferred type of polymer is an acidic ionizable cellulosic polymer with at least one ester- and / or ether-linked substituent, wherein the polymer has a degree of substitution of at least 0.05 for each substituent. Have. In the polymer nomenclature used herein, an ether-linked substituent is referred to before “cellulose” as the moiety attached to the ether group; for example, “ethyl benzoate” is ethoxybenzoate. Has a substituent. Similarly, ester-linked substituents are referred to as “carboxylic acid esters” after “cellulose”; for example, “cellulose phthalate” is one of each phthalic acid moiety ester-linked to a polymer. And other unreacted carboxylic acids.

  Polymer names such as “cellulose acetate phthalate” (CAP) are a family of cellulosic polymers that have acetic acid and phthalic acid groups attached via ester linkages to a significant fraction of the hydroxyl groups of the cellulosic polymer. It should also be noted that it means either. In general, the degree of substitution of each substituent can range from 0.05 to 2.9 as long as the other criteria of the polymer are met. “Degree of substitution” means the average number of 3 hydroxyls per saccharide repeat unit on a substituted cellulose chain. For example, all hydroxyls on the cellulose chain are phthalic acid-substituted, and the degree of phthalic acid substitution is 3. Also included within each polymer family are cellulosic polymers having additional substituents added in relatively small amounts that do not substantially alter the performance of the polymer.

  The amphiphilic cellulose derivative includes a polymer in which the cellulosic polymer has both hydrophilic and hydrophobic substituents. A hydrophobic substituent can be any substituent that, when substituted with a sufficiently high level or degree of substitution, can essentially render the cellulosic polymer essentially insoluble in water. Examples of hydrophobic substituents include ether-linked alkyl groups such as methyl, ethyl, propyl, butyl; or ester-linked alkyl groups such as acetate, propionate, butyrate; and Contains ether- and / or ester-linked aryl groups such as phenyl, benzoate or phenylate. The hydrophilic regions of the polymer can be either relatively unsubstituted moieties, or those regions substituted with hydrophilic substituents, because unsubstituted hydroxyls are themselves relatively hydrophilic. . Hydrophilic substituents include ether- or ester-linked non-ionizable groups such as hydroxyalkyl substituents, ie hydroxyethyl, hydroxypropyl, and alkyl ether groups such as ethoxyethoxy or methoxyethoxy. Particularly preferred hydrophilic substituents are those which are ether- or ester-linked ionizable groups, such as carboxylic esters, thiocarboxylic esters, substituted phenoxy groups, amines, phosphate esters or sulfonate esters. It is.

  A preferred class of acidic cellulosic polymers includes polymers that are at least partially ionizable at physiologically relevant pH, and may be either ether-linked or ester-linked, at least Contains one ionizable substituent. Examples of ether-linked ionizable substituents include: various carboxylic acids such as acetic acid, propionic acid, benzoic acid, salicylic acid, alkoxybenzoic acid such as ethoxybenzoic acid or propoxybenzoic acid, alkoxyphthalic acid Isomers such as ethoxyphthalic acid and ethoxyisophthalic acid, various isomers of alkoxynicotinic acid such as ethoxynicotinic acid, and various isomers of picolinic acid such as ethoxypicolinic acid; thiocarboxylic acids such as thioacetic acid; Phenoxy groups, such as hydroxyphenoxy; phosphoric acid, such as ethoxyphosphoric acid; and sulfonic acids, such as ethoxysulfonic acid. Examples of ester-linked ionizable substituents include: carboxylic acid esters such as succinic acid esters, citric acid esters, phthalic acid esters, terephthalic acid esters, isophthalic acid esters, trimellitic acid esters, and pyridinedicarboxylic acid Various isomers of esters; thiocarboxylic acid esters such as thiosuccinic acid esters; substituted phenoxy groups such as aminosalicylic acid esters; phosphate esters such as acetyl phosphate; and sulfonic acid esters such as acetyl sulfonate. For aromatic-substituted polymers that also have the required water solubility, sufficient hydrophilic groups such as hydroxypropyl or carboxylic acid functional groups are attached to the polymer such that at least ionizable groups are ionized. It is also desirable to make this polymer water soluble at pH values. In some cases, the aromatic substituent may itself be ionizable, such as a phthalic acid or trimellitic acid substituent.

  The polymer also contains neutral or non-ionizable substituents, which can be either ether-linked or ester-linked. Examples of ether-linked non-ionizable substituents include: alkyl groups such as methyl, ethyl, propyl, butyl and the like; hydroxyalkyl groups such as hydroxymethyl, hydroxyethyl, hydroxypropyl and the like; An aryl group such as phenyl; Examples of ester-linked non-ionizable substituents include: alkyl groups such as acetate, propionate, butyrate and the like; and aryl groups such as phenylate. However, if aryl groups are included, the polymer should contain a sufficient amount of hydrophilic substituents so that the polymer has at least some solubility in water at any physiologically relevant pH 1-8. There may be.

  Examples of cellulosic polymers at least partially ionized at physiologically relevant pH include: hydroxypropylmethylcellulose succinate, hydroxypropylmethylcellulose succinate, hydroxypropylcellulose succinate, hydroxyethylmethylcellulose succinate , Hydroxyethylcellulose succinate, hydroxypropylmethylcellulose phthalate, hydroxyethylmethylcellulose succinate, hydroxyethylmethylcellulose phthalate, carboxyethylcellulose, carboxymethylcellulose, ethylcarboxymethylcellulose, carboxymethylethylcellulose, cellulose acetate phthalate, methyl acetate phthalate Cellulose, ethyl acetate cellulose phthalate, phthalate acetate Roxypropylcellulose, hydroxypropylmethylcellulose acetate phthalate, hydroxypropylcellulose phthalate acetate, hydroxypropylmethylcellulose phthalate succinate, hydroxypropylmethylcellulose phthalate succinate, cellulose phthalate propionate, hydroxypropylcellulose phthalate butyrate, Trimellitic acid cellulose acetate, Trimethyl methyl acetate, Trimellitic acid ethyl cellulose, Trimellitic acid hydroxypropyl cellulose, Trimellitic acid hydroxypropyl methylcellulose, Trimellitic acid hydroxypropyl cellulose succinate, Trimellitic acid propionate, Trimellitic acid butyric acid cellulose, Acetic acid Cellulose terephthalate, isophthalic acid cell Loose, cellulose acetate pyridinedicarboxylate, cellulose salicylate, hydroxypropylcellulose salicylate, ethyl acetate benzoate, ethyl acetate benzoate, ethyl acetate phthalate, cellulose acetate ethyl nicotinate, and cellulose acetate picolinate .

  Examples of acidic cellulosic polymers that meet the amphiphilic definition with hydrophilic and hydrophobic regions are those in which the cellulosic repeating unit with one or more acetic acid substituents has no acetic acid substituents, Or polymers such as cellulose acetate phthalate and cellulose acetate trimellitic acid that are hydrophobic to those having one or more ionized phthalic acid or trimellitic acid substituents.

  A particularly desirable subset of cellulosic acidic polymers are those that have both carboxylic acid functional aromatic substituents and alkylated substituents, and thus are amphiphilic. Examples of polymers include cellulose acetate phthalate, methyl cellulose acetate phthalate, ethyl cellulose acetate phthalate, hydroxypropyl propyl acetate phthalate, hydroxylpropyl methylcellulose phthalate, hydroxypropyl methylcellulose phthalate acetate, hydroxypropyl cellulose succinate phthalate, propione Cellulose phthalate, hydroxypropyl cellulose butyrate phthalate, cellulose acetate trimellitic acid, methyl cellulose acetate trimellitic acid, ethyl cellulose acetate trimellitic acid, hydroxypropyl cellulose acetate trimellitic acid acetate, hydroxypropyl methylcellulose acetate trimellitic acid, hydroxypropyl cellulose succinate trimellitic acid, Trimellitic acid cellulose propionate, Cellulobutyric acid butyrate , Cellulose acetate terephthalate, cellulose acetate isophthalate, cellulose acetate pyridinedicarboxylate, cellulose acetate salicylate, hydroxypropylcellulose salicylate, cellulose acetate ethylbenzoate, ethyl acetate benzoate hydroxypropylcellulose, cellulose acetate ethylphthalate, ethyl nicotine acetate Acid cellulose and ethyl acetate picolinate.

  Another particularly desirable subset of amphiphilic cellulosic acidic polymers are those having non-aromatic carboxylic ester substituents. Examples of polymers include hydroxypropylmethylcellulose succinate, hydroxypropylmethylcellulose succinate, hydroxypropylcellulose succinate acetate, hydroxyethylmethylcellulose succinate, hydroxyethylmethylcellulose succinate, hydroxyethylcellulose succinate and carboxymethylethylcellulose.

  The inventors have found that among these cellulosic polymers that are at least partially ionized at physiologically relevant pH, the following are most preferred: hydroxypropyl methylcellulose succinate acetate, hydroxypropyl phthalate Methyl cellulose, cellulose acetate phthalate, cellulose acetate trimellitic acid and carboxymethyl ethyl cellulose. Most preferred is hydroxypropylmethylcellulose succinate acetate (HPMCAS).

  While certain polymers are believed to be suitable for use in the dosage forms of the present invention, blends of such polymers are also suitable. Thus, the term “thickened polymer” is intended to include polymer blends in addition to a single species of polymer.

  The amount of concentrated polymer relative to the amount of CETP inhibitor present in the solid drug dispersion depends on the drug and the concentrated polymer, and a drug-to-polymer mass ratio of 0.01 to 5, or about 1 to about 80 wt%. The drugs can vary widely. In most cases, however, the drug-to-polymer ratio is greater than 0.05 and less than 2.5 (about 5 to about 70 wt% drug), except when the CETP inhibitor dose is very low, for example 25 mg or less. Preferably, sometimes the drug concentration or relative bioavailability is increased by a drug-to-polymer ratio of 1 (about 50 wt% drug) or less or for some drugs 0.2 (about 17 wt% drug) or less Even less than. If the drug dose is about 25 mg or less, the drug-to-polymer mass ratio may be significantly less than 0.05. In general, regardless of dose, the increase in drug concentration or relative bioavailability increases as the drug-to-polymer mass ratio decreases. However, due to the practical limitation of keeping the total dosage form mass low, it is often desirable to use a relatively high drug-to-polymer ratio as long as satisfactory results are obtained. The maximum drug-to-polymer ratio that produces satisfactory results varies from drug to drug and is best determined in the in vitro and / or in vivo dissolution tests described below.

<Thickening>
The polymer used in the amorphous solid dispersion is a “concentrated polymer”, meaning that it meets at least one of the following conditions, and preferably both. This first condition is that the concentrated polymer increases the maximum drug concentration (MDC) of the CETP inhibitor in the environment of use relative to a control composition that contains an equivalent non-dispersible CETP inhibitor but no polymer. Is a point. That is, once the composition is introduced to the environment of use, the polymer increases the aqueous concentration of CETP inhibitor relative to the control composition. It is understood that the control composition does not contain solubilizers or other components that materially affect the solubility of the CETP inhibitor, and that the CETP inhibitor is a solid in the control composition. Control compositions are usually non-dispersed or crystalline forms of CETP inhibitor alone. Preferably, the polymer increases the MTP of the CETP inhibitor in aqueous solution by at least 1.25-fold, more preferably at least 2-fold, and most preferably at least 3-fold compared to the control composition. Surprisingly, the polymer can achieve a very large increase in aqueous concentration. In some cases, the MTP of CETP inhibitor provided by the test composition is at least 10-fold, at least 50-fold, at least 200-fold, at least 500-fold, 1000-fold the equilibrium concentration provided by the control. May be larger.

  The second condition is that the concentrated polymer has an area under the use environment concentration versus time curve (AUC) of the CETP inhibitor in the use environment and a control composition containing the non-dispersible CETP inhibitor but no polymer. It is to increase compared. (Calculation of AUC is a well-known technique in the pharmaceutical arts, for example, as described in Welling's “Pharmacokinetics Processes and Mathematics” ACS Monograph 185 (1986).) More specifically, in the environment of use, CETP The composition containing the inhibitor and the thickening polymer is any of about 0 to about 270 minutes after introduction into the environment of use, such that it is at least 1.25-times the value of the control composition described above. Provide AUC in the usage environment for 90-minutes. Preferably, the AUC in the environment of use provided by this composition is at least 2-fold, more preferably at least 3-fold that of the control composition. For some CETP inhibitors, the composition of the invention is at least 5-fold, at least 25-fold, at least 100-fold, or even 250-fold greater than the value of the control composition described above. AUC values can also be provided.

  The aforementioned “use environment” refers to an in vivo environment such as in the GI tract of an animal, particularly a human, or a test solution such as a phosphate buffered saline (PBS) solution or a fasted duodenum model (MFD) solution. Can be any of the in vitro environments.

  Enrichment may be determined by either in vivo testing or in vitro dissolution testing. The compositions of the present invention meet the concentration increase criteria in at least one of the previous test environments.

  If the environment of use is an animal GI tract, the dissolved drug concentration can be determined by routine methods known in the art. One method is the deconvolution method. In this method, serum or plasma drug concentration is plotted along the ordinate (y-axis) against blood collection time along the abscissa (x-axis). The data is then analyzed using conventional analysis such as Wagner-Nelson analysis or Loo-Riegelman analysis to determine the drug release rate in the GI tract. See also Welling's “Pharmacokinetics Processes and Mathematics” (ACS Monograph 185, Amer. Chem. Soc., Washington, D.C., 1986). Processing of data in this way results in an apparent in vivo drug release profile. Another method is to intubate the patient and periodically collect directly from the GI tract.

The amorphous solid dispersion of CETP inhibitor and concentrated polymer used in the dosage form of the present invention provides an increased concentration of dissolved CETP inhibitor in an in vitro dissolution test. Increased drug concentration in in vitro dissolution tests in MFD or PBS solutions has been determined to be a good indicator of in vivo performance and bioavailability. A suitable PBS solution is an aqueous solution containing 20 mM Na ₂ HPO ₄ , 47 mM KH ₂ PO ₄ , 87 mM NaCl, and 0.2 mM KCl adjusted to pH 6.5 with NaOH. A suitable MFD solution is the same PBS solution in which 7.3 mM sodium taurocholate and 1.4 mM 1-palmitoyl-2-oleyl-sn-glycero-3-phosphocholine are also present. In particular, the composition formed by the method of the present invention can be dissolution tested by adding it to MFD or PBS solution and stirring to promote dissolution.

  In vitro tests to assess increased concentrations of CETP inhibitors in aqueous solution are: (1) MFD or PBS, typically non-dispersible CETP inhibitors alone, to achieve equilibrium concentrations of CETP inhibitors. Addition of a sufficient amount of a control composition to an in vitro test medium, such as a solution, with stirring; (2) a sufficient amount of the test composition (eg, CETP inhibitor) in the same test medium in a separate container; And the amorphous solid dispersion of the polymer) with stirring, so that all the CETP inhibitor is dissolved, the theoretical concentration of the CETP inhibitor is at least twice the equilibrium concentration of the CETP inhibitor, Preferably at least 10 times greater; and (3) carried out by comparison of the measured MDC and / or aqueous AUC of the test composition in the test medium, at equilibrium concentrations and / or with the aqueous AUC of the control composition The When performing such dissolution tests, the amount of test or control composition used is such that when all of the CETP inhibitor is dissolved, the CETP inhibitor concentration is at least 2-fold, preferably the equilibrium concentration. The amount is at least 10-fold, most preferably at least 100-fold. In fact, for some very poorly soluble CETP inhibitors, when all the CETP inhibitors are dissolved to determine the achieved MDC, the CETP inhibitor concentration is 1000--the equilibrium concentration of the CETP inhibitor. It may be necessary to use an amount of the test composition that is twice or more.

  The concentration of dissolved CETP inhibitor is typically measured as a function of the time of collection of the test medium and plotted against the concentration of CETP inhibitor in the test medium versus time to confirm the MDC. MDC is considered to be the maximum of dissolved CETP inhibitor measured over the test period. Aqueous AUC is a concentration over any 90 minute period between the introduction of the composition into the aqueous use environment (time point equal to 0) and 270 minutes after the introduction of the composition into the use environment (time point equal to 270 minutes). Calculated by integrating the time curve. Typically, if a composition reaches its MDC rapidly, in less than about 30 minutes, the time interval used to calculate AUC is from a time equal to 0 to a time equal to 90 minutes. However, a composition formed is considered to be within the scope of the present invention if the AUC of the composition over any of the 90 minutes described above meets the criteria of the present invention.

  To avoid large drug particles that lead to erroneous decisions, the test solution is either filtered or centrifuged. “Dissolved drug” is typically considered to be a substance that passes through a 0.45 μm syringe filter or a substance that remains in the supernatant after centrifugation. Filtration can be performed using a 13 mm, 0.45 μm polyvinylidene difluoride syringe filter sold by Scientific Resources under the trademark TITAN ™. Centrifugation is typically performed by centrifuging at 13,000 G for 60 seconds in a polypropylene microcentrifuge tube. Other similar filtration or centrifugation methods can be used with useful results. For example, other types of microfilters can be used to obtain slightly higher or lower (± 10-40%) values than those obtained with the previously specified filters, but still preferred dispersions can be identified. This definition of “dissolved drug” refers not only to monomeric solvate drug molecules, but also to aggregates of drug aggregates, polymer and drug mixtures present in the filtrate or supernatant in the specified dissolution test. A wide variety of polymer / drug assemblies with dimensions smaller than micron, such as micelles, polymeric micelles, colloidal particles or nanocrystals, polymer / drug complexes, and other such drug-containing species Should also be accepted.

In another separate aspect, the amorphous solid dispersion provides an improved concentration of CETP inhibitor dissolved in blood relative to a control composition when administered orally to a fasted human or other animal. provide. Amorphous solid dispersions have CETP in blood (serum or plasma) compared to a control composition consisting of crystalline drug, which is the lowest energy form, or an equivalent of amorphous form when the crystalline form is unknown. Achieve higher maximum drug concentration (C _max ) of the inhibitor. It should be understood that the control composition does not include other ingredients that materially affect the solubility of the solubilizer or CETP inhibitor. Preferably, the amorphous solid dispersion of CETP inhibitor in the blood is at least 1.25-fold, more preferably at least 2-fold, most preferably at least 3-fold the value provided by the control composition. Provides C _max .

  Alternatively, the amorphous solid dispersion can be administered orally to humans or other animals at a value observed when a control composition comprising an equal amount of non-dispersible CETP inhibitor is administered. At least about 1.25-fold, preferably at least about 2-fold, preferably at least about 3-fold, preferably at least about 4-fold, preferably at least about 6-fold, preferably at least 10-fold, even more preferably at least Provides an AUC with a CETP inhibitor concentration in the blood that is approximately 20-fold. It is also noted that such compositions are referred to as having a relative bioavailability from about 1.25-fold to about 20-fold that of the control composition.

  The relative bioavailability of CETP inhibitors in amorphous solid dispersions can be tested in vivo in animals or humans using routine methods for making such determinations. An in vivo test such as a crossover test can be used to determine whether a CETP inhibitor and concentrated polymer composition provides enhanced relative bioavailability compared to a control composition as described above. it can. In an in vivo crossover test, a test composition of an amorphous solid dispersion of CETP inhibitor and polymer is administered to half of the test subject group, and after the appropriate washout period (e.g. one week), A control composition consisting of an equivalent amount of non-dispersible CETP inhibitor (but no polymer) is administered as the test composition. Half of the remaining groups are initially administered the control composition followed by the test composition. Relative bioavailability is measured as the area under the blood (serum or plasma) concentration versus time curve (AUC) determined for the test group divided by the AUC in the blood provided for the control composition. Preferably, this test / control ratio is determined for each subject, after which these ratios are averaged over all subjects in the test. In vivo determination of AUC can be made by plotting the serum or plasma concentration of the drug on the ordinate (y-axis) against time along the abscissa (x-axis). To facilitate dose determination, the dosage may be administered using a solvent for administration. The solvent for administration is preferably water, but in vivo these substances may contain substances that suspend the test or control composition if they do not dissolve the composition and do not alter drug solubility. Good.

<Preparation of dispersion>
Amorphous solid dispersion of CETP inhibitor and acid-concentrated polymer follows the normal process of forming an amorphous solid dispersion that produces an amorphous state of CETP inhibitor in at least a major portion (at least 60%) It may be produced. Such processes include mechanical, thermal and solvent processes. Examples of mechanical processes include grinding and extrusion; melting processes include high temperature melting, solvent-modified melting and melt-solidification processes; and solvent processes include non-solvent precipitation, spray-coating and Including spray-drying. See, for example, the following US patents, the relevant disclosures of which are incorporated herein by reference: 5,456,923 and 5,939,099, which illustrate the formation of dispersions by an extrusion process. 5,340,591 and 4,673,564, which describe the formation of dispersions by the grinding process; and 5,707,646 and 4,894,235, which describe the formation of dispersions by the melt-solidification process; .

  If the CETP inhibitor has a relatively low melting point, typically less than about 200 ° C, and preferably less than about 150 ° C, a melt-solidification or melt-extrusion process is advantageous. In such a process, the molten mixture containing the CETP inhibitor and the thickened polymer is rapidly cooled and the molten mixture is solidified to form an amorphous solid dispersion. A “molten mixture” is a mixture that contains a CETP inhibitor and a concentrated polymer such that the CETP inhibitor is substantially dispersed in one or more concentrated polymers and other excipients. Means it is heated enough to begin to become a liquid. In general, this requires that the mixture be heated about 10 ° C. or more above the melting point of the lowest melt excipient or CETP inhibitor in the composition. CETP inhibitors are present in the molten mixture as a pure phase, as a solution of CETP inhibitor dispersed homogeneously throughout the molten mixture, or in a combination of these states or intermediate states between them. May be. The molten mixture is preferably substantially homogeneous so that the CETP inhibitor is dispersed as homogeneously as possible throughout the molten mixture. When the temperature of the molten mixture is below the melting point of both the CETP inhibitor and the concentrated polymer, the melted excipient, the concentrated polymer, and the CETP inhibitor are a substantial portion of the CETP inhibitor, the concentrated polymer or It is preferred that they are sufficiently soluble in each other even though they are dispersed in the excipient. It is often preferred that the mixture be heated above the relatively low melting point of the thickening polymer and CETP inhibitor. It should be noted that many thickening polymers are amorphous. In such a case, the melting point means the softening point of the polymer. Thus, the term “melting point” generally means in particular the temperature at which a crystalline material transitions from its crystal to its liquid state, but as used herein, the term is used more broadly and in the liquid state. In a manner similar to that of the crystalline material, it means sufficient heating to start the material or material mixture becoming liquid.

  In general, the processing temperature can vary from 50 ° C. up to about 200 ° C. or higher depending on the CETP inhibitor and the melting point of the polymer, the latter being a function of the selected polymer grade. . However, the processing temperature should not be so high that unacceptable levels of CETP inhibitor or polymer degradation occur. In some cases, the molten mixture must be formed under an inert atmosphere to prevent degradation of the CETP inhibitor and / or polymer at the processing temperature. When relatively high temperatures are used, it is often preferred to minimize the time that the mixture is at an elevated temperature in order to minimize degradation.

  The molten mixture may also contain excipients that lower the melting point of the molten mixture, thereby allowing processing at lower temperatures. If such excipients have low volatility and remain substantially in the mixture upon solidification, they can generally constitute up to 30 wt% of the molten mixture. For example, a plasticizer can be added to the mixture to reduce the melting point of the polymer. Examples of plasticizers are water, triethyl citrate, triacetin and dibutyl sebacate. Volatiles that dissolve or swell this polymer, such as acetone, water, methanol and ethyl acetate, can also be added to lower the melting point of the molten mixture. When such volatile excipients are added, at least some, and at most essentially all such excipients may be evaporated during or after the conversion of the molten mixture to a solid mixture. . In such cases, the treatment is considered a combination of solvent process and melt-solidification or melt-extrusion. Removal of such volatile excipients from the molten mixture can be achieved by discrete or atomization of the molten mixture into small droplets, as well as cooling the droplets and losing all or part of the volatile excipients. This can be achieved by contact of the droplets with the liquid. Examples of other excipients that can be added to the mixture to reduce the processing temperature include low molecular weight polymers or oligomers such as polyethylene glycol, polyvinyl pyrrolidone, and poloxamers; mono-, di-, and triglycerides, Fats and oils; natural and synthetic waxes such as carnauba wax, beeswax, microcrystalline wax, castor wax and paraffin wax; long chain alcohols such as cetyl alcohol and stearyl alcohol; and long chain fatty acids such as stearic acid. As mentioned above, if the added excipient is volatile, it can be removed from the mixture while still molten or subsequently solidified to form an amorphous solid dispersion.

  Virtually any process can be used to form a molten mixture. One method involves melting the thickened polymer in the container, followed by the addition of CETP inhibitor to the molten polymer. Another method is the melting of the CETP inhibitor in the container followed by the addition of a thickening polymer. In yet another method, a solid blend of CETP inhibitor and thickened polymer is added to the container and the blend is heated to form a molten mixture.

  Once the molten mixture is formed, it can be mixed to ensure that the CETP inhibitor is homogeneously dispersed throughout the molten mixture. Such mixing can be performed using mechanical means such as a mixer and stir bar driven by a magnet, a planetary mixer, and a homogenizer. Optionally, once the molten mixture is formed in the container, the contents of the container are pumped out of the container, passed through a row or stationary mixer, and then returned to the container. The amount of shear used to mix the molten mixture must be high enough to ensure uniform distribution of the CETP inhibitor in the molten mixture. The molten mixture can be mixed for several minutes to several hours, with the mixing time depending on the viscosity of the mixture and the solubility of the CETP inhibitor and the presence of any excipients in the concentrated polymer.

  Yet another method of preparing the molten mixture uses two containers, melting the CETP inhibitor in the first container and the concentrated polymer in the second container. The two melts are then pumped through a row of stationary mixers and extruders to form a molten mixture that is then rapidly solidified.

  Yet another method of preparing the molten mixture is the use of an extruder, such as a single screw or twin screw extruder, both well known in the art. In such an apparatus, a solid feed of the composition is fed to an extruder, whereby the combination of heat and shear forces forms a uniformly mixed molten mixture that is then rapidly solidified and non- A crystalline solid dispersion is formed. The solid feed can be prepared using methods well known in the art to obtain a solid mixture with high content uniformity. Alternatively, the extruder is equipped with two feeders, allowing the CETP inhibitor to pass through one feeder and the polymer to be fed into the extruder through the other. In the case where another excipient for lowering the processing temperature as described above is included in the solid feed or is a liquid excipient such as water, extrusion may be performed using methods well known in the art. It may be injected into the machine.

  The extruder must be designed to produce a molten mixture with CETP inhibitor uniformly dispersed throughout the composition. The various zones of the extruder are heated to the appropriate temperature using techniques well known in the art to obtain the desired degree of mixing or shear in addition to the desired extrusion temperature.

  If the CETP inhibitor has a high solubility in the concentrated polymer, a relatively low amount of mechanical energy will be required to form an amorphous solid dispersion. If the melting point of the non-dispersible CETP inhibitor is higher than the melting point of the non-dispersed concentrated polymer, the processing temperature is lower than the melting point of the non-dispersible CETP inhibitor but higher than the melting point of the polymer, The reason is that the CETP inhibitor dissolves in the molten polymer. If the melting point of the non-dispersible CETP inhibitor is lower than the melting point of the non-dispersible concentrated polymer, the processing temperature is higher than the melting point of the non-dispersible CETP inhibitor, but Below the melting point, because the melted CETP inhibitor is dissolved or absorbed in the polymer.

  If the CETP inhibitor has low solubility in the polymer, a larger amount of mechanical energy is required to form an amorphous solid dispersion. Here, the treatment temperature needs to be higher than the melting point of the CETP inhibitor and the polymer. As mentioned above, liquid or low-melting excipients may be added instead that promote melting or mutual dissolution of the thickened polymer and CETP inhibitor. A large amount of mechanical energy is also required to mix the CETP inhibitor and polymer and form a dispersion. Typically, the lowest processing temperature and lowest mechanical energy that produces a satisfactory dispersion (substantially amorphous and substantially homogeneous) to minimize exposure of the CETP inhibitor to harsh conditions That is, an extruder design that provides shear is selected.

  Once a molten mixture of CETP inhibitor and thickened polymer is formed, the mixture must rapidly solidify to form an amorphous solid dispersion. “Rapid solidification” means that the molten mixture solidifies fast enough that no substantial phase separation of the CETP inhibitor and polymer occurs. Typically this means that the mixture solidifies within about 10 minutes, preferably within about 5 minutes, more preferably within about 1 minute. If the mixture does not solidify quickly, phase separation occurs, resulting in the formation of CETP inhibitor-rich and polymer-rich phases.

  Solidification often occurs primarily by cooling the molten mixture to at least about 10 ° C., preferably at least about 30 ° C. below its melting point. As mentioned above, solidification can be further facilitated by evaporation of all or part of one or more volatile excipients or solvents. To facilitate rapid cooling and evaporation of volatile excipients, the molten mixture is often made into high surface area shapes, such as rods or fibers or droplets. For example, the molten mixture applies force through one or more small holes to form elongated fibers or rods, or an atomizer such as a rotating plate that pulverizes the molten mixture into droplets having a diameter of 1 μm to 1 cm. Can be supplied to the device. The droplets are then contacted with a relatively cool fluid such as air or nitrogen to facilitate cooling and evaporation.

A useful tool for evaluating and selecting conditions for forming a substantially homogeneous, substantially amorphous dispersion by a melt-solidification or melt-extrusion process is the differential scanning calorimeter (DSC). . While the rate at which the sample is heated and cooled in DSC is limited, it allows for precise control of the thermal history of the sample. For example, the CETP inhibitor and the thickening polymer are dry-blended and then placed in a DSC sample pan. The DSC is then programmed to heat the sample at the desired rate, maintain the sample at the desired temperature for the desired time, and then quickly cool to ambient or lower. The sample was then reanalyzed on the DSC to prove that it was converted to a substantially homogeneous, substantially amorphous dispersion (ie, the sample has a single T _g ). Using this approach, the temperature and time required to achieve a substantially homogeneous, substantially amorphous dispersion for the CETP inhibitor and the concentrated polymer is determined.

Another method of forming an amorphous solid dispersion is by “solvent treatment”, which consists of dissolving a CETP inhibitor and one or more polymers in a common solvent. “Common” means here that the solvent, which can be a mixture of compounds, dissolves both the CETP inhibitor and the polymer (s). After both the CETP inhibitor and the polymer are dissolved, the solvent is rapidly removed by evaporation or by mixing with a non-solvent. Illustrative techniques are spray-drying, spray-coating (pan-coating, fluid bed coating, etc.), and rapid mixing of polymers and CETP inhibitor solutions with CO ₂ , water, or some other non-solvent. It is sedimentation. Preferably, removal of the solvent results in the formation of a substantially homogeneous amorphous solid dispersion. In such a dispersion, the CETP inhibitor is dispersed as homogeneously as possible throughout the polymer and can be considered as a solid solution of CETP inhibitor dispersed in the polymer (s), where an amorphous solid The dispersion is thermodynamically stable, which means that the concentration of CETP inhibitor in the polymer is at or below its equilibrium value, or CETP inhibitor in the concentrated polymer (s) It is considered to be a supersaturated solid solution whose concentration exceeds its equilibrium value.

  The solvent can be removed by spray-drying. The term “spray-drying” is used in its usual broad sense, a spray-drying device in which there is a strong driving force for the crushing (nebulization) of a liquid mixture into small droplets and evaporation of the solvent from the droplets. It means a process related to rapid solvent removal from the mixture in it. The spray-drying process and spray-drying apparatus are generally described in Perry's “Chemical Engineers' Handbook” pages 20-54 to 20-57 (6th edition, 1984). More detailed spray-drying processes and equipment are described in Marshall's “Atomization and Spray-Drying” 50 Chem. Eng. Prog. Monogr. Series 2 (1954), and Masters “Spray-Drying Handbook” (4th edition, 1985). Has been verified. A strong driving force for solvent evaporation is generally provided by maintaining a partial pressure of the solvent in the spray-drying apparatus that is well below the vapor pressure of the solvent at the temperature of the dry droplets. This may be (1) maintenance of pressure in a spray-drying device at incomplete vacuum (eg 0.01 to 0.50 atm); or (2) mixing of liquid droplets with warm drying gas; or (3) Realized by both (1) and (2). In addition, at least a portion of the heat required for solvent evaporation may be provided by heating the spray solution.

  Suitable solvents for spray-drying may be any CETP inhibitor and an organic compound in which the polymer is both soluble. Preferably the solvent is also volatile with a boiling point of 150 ° C. or less. In addition, the solvent is relatively toxic and is removed from the amorphous solid dispersion to an acceptable level according to the “ICH guidelines”. Removal of the solvent to this level requires subsequent processing steps such as shelf-drying. Preferred solvents are alcohols such as methanol, ethanol, n-propanol, isopropanol, and butanol; ketones such as methyl ethyl ketone and methyl iso-butyl ketone; esters such as ethyl acetate and propyl acetate; and various other solvents such as acetonitrile, chloride, There are methylene, toluene, tetrahydrofuran, and 1,1,1-trichloroethane. Lower volatile solvents such as dimethylacetamide or dimethyl sulfoxide can also be used. Solvent mixtures such as 50% methanol and 50% acetone can also be used, such as a mixture with water, as long as the polymer and CETP inhibitor are sufficiently soluble to perform the spray-drying process practice. . In general, due to the hydrophobic nature of low-solubility CETP inhibitors, non-aqueous solvents are preferred, which means that the solvent contains less than about 10 wt% water.

  Solvent-carrying feed materials containing CETP inhibitors and thickened polymers can be spray-dried under a wide variety of conditions to obtain dispersions with more acceptable properties. For example, various types of nozzles can be used to spray the spray solution, which introduces the spray solution into the spray-drying chamber as a collection of small droplets. As long as the droplets formed are sufficiently dry (due to solvent evaporation) that do not adhere or cover the walls of the spray-drying chamber, essentially any type of nozzle can be used to spray the solution. Can be used.

  The maximum droplet size varies widely as a function of size, shape and flow pattern within the spray-dryer, but generally droplets are less than about 500 μm in diameter when exiting the nozzle. Examples of types of nozzles that can be used to form an amorphous solid dispersion include two-fluid nozle, fountain nozzle, flat fan nozzle, pressure nozzle, and rotary nozzle Includes atomizer. In a preferred embodiment, a pressure nozzle is used, as disclosed in co-pending application US Pat. No. 60 / 353,986, assigned to the assignee of the present invention, the disclosure of which is hereby incorporated by reference. Incorporated as a reference.

  The spray solution can be delivered to one or more spray nozzles over a wide range of temperatures and flow rates. In general, the spray solution temperature is from just above the freezing point of the solvent to about 20 ° C. above its ambient pressure boiling point (due to the pressurization of the solution) and in some cases even higher. The flow rate of spray solution to the spray nozzle can vary widely depending on the type of nozzle, spray-dryer size and spray-drying conditions such as inlet temperature and drying gas flow rate. In general, the energy for evaporation of the solvent from the spray solution in the spray-drying process comes mainly from the drying gas.

  The drying gas may in principle be essentially any gas, but for safety reasons and to minimize unwanted oxidation of CETP inhibitors or other materials in the amorphous solid dispersion Inert gases such as nitrogen, nitrogen-rich air or argon are used. The drying gas is typically introduced into the drying chamber at a temperature of about 60 ° C. to about 300 ° C., preferably about 80 ° C. to about 240 ° C.

  The large surface area to volume ratio of the droplets and the large driving force of solvent evaporation lead to rapid solidification time of the droplets. The solidification time should be less than about 20 seconds, preferably less than about 10 seconds, more preferably less than 1 second. This rapid solidification is often important for particles that maintain a homogeneous homogeneous dispersion instead of separating into a CETP inhibitor rich phase and a polymer-rich phase. In a preferred embodiment, the height and volume of the spray-dryer is adjusted to provide sufficient time for the droplets to dry before impinging on the inner surface of the spray-dryer, which is U.S. Provisional Application No. 60 / 354,080, assigned to the assignee, which is a co-pending application, and is described in detail in what is currently published as U.S. Patent Application No. 20030163931. Incorporated herein by reference. As mentioned above, it is often necessary to obtain a dispersion that is as homogeneous as possible in order to obtain large increases in concentration and bioavailability.

  After solidification, the solid powder is typically present in the spray-drying chamber for about 5-60 seconds, further evaporating the solvent from the solid powder. The final solvent content of the solid dispersion is low when it exits the dryer because it reduces the mobility of CETP inhibitor molecules in the amorphous solid dispersion, thereby making it stable It is because it improves. In general, the content of solvent in the amorphous solid dispersion as it exits the spray-drying chamber should be less than 10 wt%, preferably less than 2 wt%. After formation, the amorphous solid dispersion is dried and the remaining solvent is shelf drying, fluid bed drying, microwave drying, belt drying, rotary drying, and other drying processes known in the art, It is removed using a suitable drying process.

  Amorphous solid dispersions are usually in the form of small particles. The average size of the particles may be less than 500 μm in diameter, or less than 100 μm in diameter, 50 μm in diameter, or less than 25 μm in diameter. When an amorphous solid dispersion is formed by spray-drying, the resulting dispersion is in the form of such small particles. When the amorphous solid dispersion is formed by other methods, such as a melt-solidification or extrusion process, the resulting dispersion obtains a large number of small particles by sieving, grinding, or another treatment.

  Once an amorphous solid dispersion containing a CETP inhibitor and a thickened polymer is formed, several processing operations can be used to facilitate incorporation of the dispersion into the dosage form. These processing operations include drying, granulation and grinding.

  Amorphous solid dispersions may be granulated to increase particle size and improve the handling of this dispersion in forming suitable dosage forms. Preferably, the average size of the granules is in the range of 50-1000 μm. Such a granulation process can be performed before or after the composition is dried, as described above. A dry or wet granulation process can be used for this purpose. An example of a dry granulation process is roller compaction. The wet granulation process can include fluid bed granulation in addition to so-called low shear and high shear granulation. In these processes, the granulating liquid is mixed into the composition after the dry ingredients are blended to assist in the formation of the granulated composition. Examples of granulating liquids are water, ethanol, isopropyl alcohol, n-propanol, various isomers of butanol, and mixtures thereof.

  If a wet granulation process is used, the granulated composition is often dried prior to further processing. Examples of suitable drying processes used in combination with wet granulation are the same as described above. If the amorphous solid dispersion is formed by a solvent process, the composition can be granulated prior to removal of residual solvent. During the drying process, residual solvent and granulating liquid are simultaneously removed from the composition.

  Once the composition has been granulated, it is then milled to achieve the desired particle size. Examples of suitable processes for grinding the composition include hammer mills, ball mills, fluid-energy mills, roller mills, cutting mills, and other grinding processes known in the art.

  The process of forming an amorphous solid dispersion of CETP inhibitor and thickened polymer is described in co-pending US patent application Ser. Nos. 09 / 918,127 and 10 / 066,091, assigned to the assignee of the present invention. Which are described in detail and are incorporated herein by reference.

<HMG-CoA reductase inhibitor>
The HMG-CoA reductase inhibitor may be either a low-density lipoprotein, total cholesterol, or an HMG-CoA reductase inhibitor capable of reducing the plasma concentration of both. HMG-CoA reductase inhibitors are acid-sensitive, meaning that the drug chemically reacts or otherwise degrades in the presence of acidic species. Examples of chemical reactions include hydrolysis, lactonization, or transesterification in the presence of acidic species.

  In one aspect, HMG-CoA reductase inhibitors are derived from a class of therapeutics commonly referred to as statins. Examples of HMG-CoA reductase inhibitors that can be used include lovastatin (see MEVACOR ™; US Pat. Nos. 4,231,938; 4,294,926; 4,319,039), simvastatin (ZOCOR ™; US Pat. No. 4,444,784). 4,450,171; 4,820,850; see 4,916,239), pravastatin (PRAVACHOL ™; US Pat. Nos. 4,346,227; 4,537,859; 4,410,629; 5,030,447 and 5,180,589), pravastatin Lactones (see U.S. Pat. No. 4,448,979), fluvastatin (LESCOL (TM); U.S. Pat. Nos. 5,354,772; 4,911,165; 4,739,073; 4,929,437; 5,189,164; 5,118,853; 5,290,946; 5,356,896), lactones of fluvastatin, atorvastatin (LIPITOR ™; US Pat. Nos. 5,273,995; 4,681,893; 5,489,691; 5,342,952), lactones of atorvastatin, cerivastatin (also rivasta) And also known as BAYCHOL ™; see US Pat. No. 5,177,080 and European Patent Application EP-491226A), lactones of cerivastatin, rosuvastatin (Crestor ™; US Pat. Nos. 5,260,440 and RE37314) As well as rosuvastatin lactone, itavastatin, nisvastatin, visastatin, atavastatin, velvastatin, compactin, dihydrocompactin, dalvastatin, fluindostatin, pitivastatin ), Mevastatin (see US Pat. No. 3,983,140), and velostatin (referred to as symvinolin), but is not limited thereto. Examples of other HMG-CoA reductase inhibitors are US Pat. Nos. 5,217,992; 5,196,440; 5,189,180; 5,166,364; 5,157,134; 5,110,940; 5,106,992; 5,099,035; No. 5,049,696; No. 5,049,577; No. 5,025,017; No. 5,011,947; No. 5,010,105; No. 4,970,221; No. 4,940,800; No. 4,866,058; No. 4,686,237; No. 4,647,5762; European Patent Application No. 0142146A2 And PCT application publications 86/03488 and 86/07054. Also included are the pharmaceutically acceptable forms described above. All of the above references are incorporated herein by reference. Preferably, the HMG-CoA reductase inhibitor is fluvastatin, lovastatin, pravastatin, atorvastatin, simvastatin, cerivastatin, rivastatin, mevastatin, verostatin, compactin, dalvastatin, fluindostatin, rosuvastatin, pitivastatin, dihydrocompactin and Selected from the group consisting of: pharmaceutically acceptable forms. “Pharmaceutically acceptable form” refers to any pharmaceutically acceptable derivative, including stereoisomers, stereoisomer mixtures, enantiomers, solvates, hydrates, isomorphs, polymorphs, salt forms and prodrugs. Or a variant.

  A test to determine whether an HMG-CoA reductase inhibitor is acid sensitive administers this drug in an acidic aqueous solution and plots the drug concentration versus time. The acidic solution must have a pH of 1-4. HMG-CoA reductase inhibitors that are acid sensitive are those in which the drug concentration decreases by at least 1% within 24 hours of drug administration to an acidic solution. A drug is “slightly acid-sensitive” if it changes 1% within 6-24 hours. A drug is “moderately acid-sensitive” if the drug concentration changes by 1% within a period of 1-6 hours. A drug is “highly acid-sensitive” if the drug concentration changes by 1% within an hour. The present invention recognizes that the availability of HMG-CoA reductase inhibitors that are slightly acid-sensitive, moderately acid-sensitive and highly acid-sensitive is increased.

  In one embodiment, the HMG-CoA reductase inhibitor is trans-6- [2- (3 or 4-carboxyamido-substituted pyrrol-1-yl) alkyl] -4-hydroxypyran-2-one. And the corresponding pyran ring-opened hydroxy acid derived therefrom. These compounds are described in US Pat. No. 4,681,893, which is hereby incorporated by reference. The pyran ring-opened hydroxy acid, which is an intermediate for the synthesis of lactone compounds, can be used as the free acid or as a pharmaceutically acceptable metal or amine salt. In particular, these compounds can be represented by the following structure:

[In the formula, _{X, -CH 2 -, - CH 2} CH 2 -, - CH 2 CH 2 CH 2 - or -CH ₂ CH (CH ₃₎ - a and; R ₁ is 1-naphthyl; 2- Cyclohexyl, norbornenyl; 2-, 3- or 4-pyridinyl; phenyl; fluorine, chlorine, bromine, hydroxyl, trifluoromethyl, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, Or phenyl substituted with an alkanoylalkoxy of 2 to 8 carbon atoms; either R ₂ or R ₃ is —CONR ₅ R ₆ , wherein R ₅ and R ₆ are independently hydrogen Alkyl with 1-6 carbon atoms; 2-, 3-, or 4-pyridinyl; phenyl; substituted with fluorine, chlorine, bromine, cyano, trifluoromethyl, or carboalkoxy with 3-8 carbon atoms; be phenyl; and, other than the R ₂ or R ₃ is hydrogen; cyclopropyl; alkyl of 1 to 6 carbon atoms Shikurobuchi Cyclopentyl; cyclohexyl; phenyl; or fluorine, chlorine, bromine, hydroxyl, trifluoromethyl, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, or 2 to 8 carbon atoms R ₄ is alkyl of 1 to 6 carbon atoms; cyclopropyl; cyclobutyl; cyclopentyl; cyclohexyl; or trifluoromethyl; and M is pharmaceutically acceptable A salt (eg, a counter ion), which includes a pharmaceutically acceptable metal salt or a pharmaceutically acceptable amine salt. ].

Of the stereospecific isomers, one preferred HMG-CoA reductase inhibitor is atorvastatin hemi-calcium salt trihydrate. This preferred compound is a ring-opened (2R-trans) -5- (4-fluorophenyl) -2- (1-methylethyl) -N, 4-diphenyl-1- [2- (tetrahydro-4 -Hydroxy-6-oxo-2H-pyran-2-yl) ethyl] -1H-pyrrole-3-carboxamide, ie the enantiomer [R- (R ^* , R ^* )]-2- (4-fluorophenyl-β , δ-dihydroxy-5- (1-methylethyl) -3-phenyl-4-[(phenylamino) carbonyl)]-1H-pyrrole-1-heptanoic acid hemi-calcium salt. Its chemical structure is represented by the following structure.

This specific isomer is disclosed in US Pat. No. 5,273,995, which is incorporated herein by reference. In a preferred embodiment, the HMG-CoA reductase inhibitor is atorvastatin, the cyclized lactone form of atorvastatin, 2-hydroxy, 3-hydroxy or 4-hydroxy derivatives of such compounds, and pharmaceuticals thereof. Selected from the group of acceptable shapes.

  Indeed, the use of this salt form reaches the sum of the use of the acid or lactone form. Suitable pharmaceutically acceptable salts within the scope of the present invention include sodium hydroxide, potassium hydroxide, lithium hydroxide, calcium hydroxide, 1-deoxy-2- (methylamino) -D-glucitol, magnesium hydroxide, It is derived from a base such as zinc hydroxide, aluminum hydroxide, ferrous or ferric hydroxide, ammonium hydroxide, or organic amines such as N-methylglucamine, choline, arginine. Preferably, lithium, calcium, magnesium, aluminum and ferrous or ferric salts are prepared from sodium or potassium salts by adding a suitable reagent to the sodium or potassium salt solution, i.e., chloride. Addition of calcium to a solution of the sodium or potassium salt of a compound of formula A will yield those calcium salts.

<Preparation of unit dosage form>
The unit dosage form comprises a CETP inhibitor composition, an HMG-CoA reductase inhibitor composition, and in this dosage form, the amorphous solid dispersion and the HMG-CoA reductase inhibitor are substantially separated from each other. Formed together. As previously noted, the substantial separation is achieved when a sufficient amount of HMG-CoA reductase inhibitor is physically separated from the amorphous solid dispersion and the acid-concentrated polymer is at an unacceptable level of HMG-CoA reductase. Means that it does not cause chemical degradation of the inhibitor. The improved chemical stability of this HMG-CoA reductase inhibitor is mainly due to the proportion of HMG-CoA reductase inhibitor molecules in contact with the amorphous solid dispersion of CETP inhibitor / acid-concentrated polymer. Related to decline.

  For some unit dosage forms, the separation is macroscopic in nature; that is, the HMG-CoA reductase inhibitor and the amorphous solid dispersion are physically separated. This is the case, for example, when an HMG-CoA reductase inhibitor and an amorphous solid dispersion are placed in a separate layer of the dosage form, so that such an HMG-CoA reductase present at the boundary of the two layers Only the inhibitor molecule can be achieved by contact with the amorphous solid dispersion. Further separation between the HMG-CoA reductase inhibitor and the amorphous solid dispersion may be obtained by providing a third layer that separates the two compositions. Alternatively, the unit dosage form may be in the form of a kit where the HMG-CoA reductase inhibitor and the amorphous solid dispersion are present in separate compartments in the dosage form. Further details of unit dosage forms in which the separation is macroscopic in nature are described below.

  For other unit dosage forms, the separation is microscopic in nature; that is, the separation may simply be by one or more intervening molecules. This is the case when the dosage form contains a mixture of particles or granules. For example, a unit dosage form can comprise a number of relatively large particles or granules comprising an amorphous solid dispersion of a CETP inhibitor and an HMG-CoA reductase inhibitor. HMG-CoA reductase inhibitor molecules located inside the particle or granule are separated from the amorphous solid dispersion of CETP inhibitor by those molecules on the surface of the particle or granule. Furthermore, inclusion of excipients in particles or granules containing HMG-CoA reductase inhibitors reduces the number of molecules of HMG-CoA reductase inhibitors on the surface of the particles or granules, and HMG-CoA reductase Further separation of the inhibitor from the amorphous solid dispersion will result.

  Alternatively, the amorphous solid dispersion of CETP inhibitor can be in the form of relatively large particles or granules, and the molecules of the acidic concentrated polymer in the amorphous solid dispersion inside the granule particles Alternatively, these molecules on the surface of the granules are separated from the HMG-CoA reductase inhibitor. Inclusion of the granulating excipient in the particles or granules further reduces the amorphous solid dispersion fraction on the surface of the particles or granules.

  Alternatively, the HMG-CoA reductase inhibitor particles or granules, the amorphous solid dispersion particles or granules, or both may be coated with a protective coating so that the HMG-CoA reductase inhibitor and non- The crystalline solid dispersion is separated. In either case, the HMG-CoA reductase inhibitor and the amorphous solid dispersion are substantially separated from each other, so that the acid-concentrated polymer has an unacceptable level of HMG-CoA reductase inhibitor. Does not cause chemical degradation.

  The amount of CETP inhibitor and HMG-CoA reductase inhibitor present in the dosage form will vary depending on the desired dose of each compound, which in turn will depend on the potency of the compound and the condition being treated. fluctuate. For example, [2R, 4S] -4-[(3,5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline The desired dosage of torcetrapib, a CETP inhibitor also known as -1-carboxylic acid ethyl ester, is 1 mg / day to 1000 mg / day, preferably 10 to 250 mg / day, more preferably 30 to 90 mg / day. It is a range. For atorvastatin calcium, which is an HMG-CoA reductase inhibitor, the dosage ranges from 1 to 160 mg / day, preferably from 2 to 80 mg / day. For the HMG-CoA reductase inhibitors lovastatin, pravastatin sodium, simvastatin, rosuvastatin calcium, and fluvastatin sodium, the dosage varies from 2 to 160 mg / day, preferably from 10 to 80 mg / day. For cerivastatin sodium, which is an HMG-CoA reductase inhibitor, the dosage varies from 0.05 to 1.2 mg / day, preferably from 0.1 to 1.0 mg / day.

  The CETP inhibitor composition contains optional excipients depending on the amorphous solid dispersion and the type of dosage form to be prepared. The amount of amorphous solid dispersion present in the CETP inhibitor composition may vary according to the desired dosage of CETP inhibitor. In one aspect, the CETP inhibitor composition has a high load of amorphous solid dispersion. High loading of the dispersion in the composition will minimize the size of the dosage form, make it easier to swallow, and improve patient compliance. Depending on the dose of CETP inhibitor, the amorphous solid dispersion may comprise at least 30 wt% CETP inhibitor composition. More preferably, the amorphous solid dispersion may comprise at least 40 wt% CETP inhibitor composition, most preferably at least 50 wt%.

  In addition to the amorphous solid dispersion, the CETP inhibitor composition can also include a disintegrant. Inclusion of the disintegrant in the CETP inhibitor composition facilitates rapid dissolution of the dosage form when introduced into an aqueous use environment. Examples of disintegrants are sodium starch glycolate, sodium carboxymethylcellulose, carboxymethylcellulose calcium, internally cross-linked camelose sodium, internally cross-linked povidone, polyvinylpolypyrrolidone, methylcellulose, microcrystalline cellulose, powdered cellulose, lower alkyl-substituted Hydroxypropylcellulose, polacrilin potassium, starch, ungelatinized starch, sodium alginate, and mixtures thereof. Of these, internally cross-linked povidone, internally cross-linked carmellose sodium, lower alkyl-substituted hydroxypropylcellulose, methylcellulose, polacrilin potassium, and mixtures thereof are preferred, and internally cross-linked povidone and internally cross-linked carmellose sodium are most preferred. . The amount of disintegrant contained in the dosage form depends on several factors, including the amorphous solid dispersion present in the composition, the characteristics of other excipients, and the CETP inhibitor from the dosage form. Including the desired release rate. Generally, the disintegrant will comprise 1 wt% to 25 wt%, preferably 5 wt% to 20 wt% of the CETP inhibitor composition.

  The CETP inhibitor composition may contain a porosifying agent. A “porosigen” is a material that, when present in a formulation containing an amorphous solid dispersion, leads to high porosity and high strength after compression of this formulation into a tablet. . In addition, preferred porogens are soluble in acidic environments and have a solubility in water of less than about pH 4, typically greater than 1 mg / mL. In general, the main deformation mechanism of a porous agent under compression is brittle fracture rather than plastic flow. Examples of porosifying agents are gum arabic, calcium carbonate, calcium sulfate, calcium sulfate dihydrate, compressed sugar, dibasic calcium phosphate (anhydrous and dihydrate), tribasic calcium phosphate, monobasic phosphate There are sodium, dibasic sodium phosphate, lactose, magnesium oxide, magnesium carbonate, silicon dioxide, magnesium aluminum silicate, maltodextrin, mannitol, methylcellulose, microcrystalline cellulose, sorbitol, sucrose and xylitol. Of these, both microcrystalline cellulose and dibasic calcium phosphate (anhydrous and dihydrate) forms are preferred. As with the choice of disintegrant, the amount of porosifying agent included in the dosage form will depend on the characteristics of the amorphous solid dispersion, the disintegrant selected and the porogen. Generally, the porosifying agent will comprise 5 to 70 wt% of the dosage form, preferably 10 to 50 wt%.

  Other conventional formulation excipients can be used in CETP inhibitor compositions, which are well known in the art, for example as described in "Remington's Pharmaceutical Sciences" (18th edition, 1990). Of such excipients. In general, excipients such as surfactants, pH regulators, fillers, base materials, complexing agents, solubilizers, pigments, lubricants, glidants, flavoring agents, etc. for normal purposes, It can be used in typical amounts that do not have a deleterious effect on the properties of the composition.

  One very useful excipient type is a surfactant, preferably present at 0-10 wt%. Suitable surfactants include fatty acids and alkyl sulfonates; commercially available surfactants such as benzalkonium hydrochloride (HYAMINE ™ 1622, Lonza, Fairlawn, NJ); dioctyl sodium sulfosuccinate (DOCUSATE SODIUM, Mallinckrodt Specialty Chemical St. Louis, MO); polyoxyethylene sorbitan fatty acid ester (TWEEN ™, ICI Americas, Wilmington, DE; LIPOSORB ™ 0-20, Lipochem, Patterson, NJ; CAPMUL ™ POE- 0, Abitec, Janesville, WI); natural surfactants such as sodium taurocholate, 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine, lecithin, and other phospholipids and mono- and Diglycerides; and polyoxyethylene-polyoxypropylene. Such materials can be advantageously used, for example, to increase the dissolution rate by assisting wetting, or otherwise increase the release rate of the CETP inhibitor from the dosage form.

  Inclusion of pH adjusting agents such as acids, bases, or buffers is beneficial in amounts of 0-10 wt%. Acidic pH modifiers (eg, acids such as citric acid or succinic acid) inhibit dissolution of amorphous solid dispersions containing CETP inhibitors and acidic thickening polymers.

  In a preferred embodiment, the CETP inhibitor composition also includes a base. Inclusion of the base results in an increase in pH in the vicinity of the acidic concentrated polymer, which leads to improved chemical stability of the HMG-CoA reductase inhibitor. The term “base” is used broadly to include not only strong bases such as sodium hydroxide, but also weak bases and buffers that are capable of achieving the desired increase in chemical stability. Examples of bases are hydroxides such as sodium hydroxide, calcium hydroxide, ammonium hydroxide, and choline hydroxide; bicarbonates such as sodium bicarbonate, potassium bicarbonate, and ammonium bicarbonate; carbonates such as carbonate Ammonium, calcium carbonate, and sodium carbonate; amines such as tris (hydroxymethyl) aminomethane, ethanolamine, diethanolamine, N-methylglucamine, glucosamine, ethylenediamine, N, N'-dibenzylethylenediamine, N-benzyl-2- Phenethylamine, cyclohexylamine, cyclopentylamine, diethylamine, isopropylamine, diisopropylamine, dodecylamine, and triethylamine; proteins such as gelatin; amino acids such as lysine, arginine, guanine, glycine And amines; polymeric amines such as polyaminomethacrylate, Eudragit E, etc .; conjugate bases of various acids such as sodium acetate, sodium benzoate, ammonium acetate, disodium phosphate, trisodium phosphate, calcium hydrogen phosphate, Includes sodium phenolate, sodium sulfate, ammonium chloride, and ammonium sulfate; salts of EDTA such as tetrasodium EDTA; and salts of various acidic polymers such as sodium starch glycolate, sodium carboxymethylcellulose and sodium polyacrylate. In one embodiment, the base partially neutralizes the acidic thickened polymer. “Partial neutralization” means that the base causes at least some of the acidic moieties or acidic substituents on the acidic concentrated polymer to be present in a deprotonated form. Such a neutralized acidic polymer is a U.S. provisional application filed Dec. 20, 2002, assigned to the assignee of the present invention, entitled `` Dosage Formss Comprising a CETP Inhibitor and an HMG-CoA Reductase Inhibitor ", US Provisional Application No. 60 / 435,298, which is incorporated herein by reference. In a preferred embodiment, the base is present in an amount such that there is a molar excess over the acidic substituents on the dispersion polymer.

  Examples of other base materials, fillers or diluents include dextrose, compressed sugar, lactose hydrate, corn starch, silicic anhydride, polysaccharides, dextrates, dextran, dextrin, dextrose, calcium carbonate, calcium sulfate, poloxamer, And polyethylene oxide.

  Another optional excipient comprises a binder such as methylcellulose, carboxymethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, polyvinyl alcohol or starch.

  Examples of drug-complexes or solubilizers include polyethylene glycol, caffeine, xanthan, gentisic acid and cyclodextrin.

  Examples of lubricants are calcium stearate, glyceryl monostearate, glyceryl palmitostearate, hydrogenated vegetable oil, light oil, magnesium stearate, mineral oil, polyethylene glycol, sodium benzoate, sodium lauryl sulfate, sodium aryl fumarate , Stearic acid, talc and zinc stearate.

  Examples of glidants are silicon dioxide, talc and corn starch.

  CETP inhibitor compositions can be formed according to any conventional method. In one embodiment, the composition is formed by blending an amorphous solid dispersion and optional excipients using techniques well known in the art (e.g., `` Remington's Pharmaceutical Sciences '' (18th edition)). , 1990)). Examples of blenders are twin-shell blenders, fluidized beds, and V blenders.

  In another embodiment, the composition is granulated. Illustrative methods are wet-granulation and dry-granulation. The amorphous solid dispersion is granulated with or without the addition of other optional excipients. For example, an amorphous solid dispersion, a disintegrant, and a porogen are formed into granules by mechanical means such as roller compaction or “slagging” followed by granulation by grinding. Granules typically have improved flow, handling, blending, and compression properties compared to non-granulated materials. Wet granulation techniques are also used if the selected solvent and process do not change the properties of the amorphous solid dispersion. When wet granulation is used, the granulating liquid is typically removed from the granule during or after the granulation process. The granules so formed typically have an average diameter of 50 μm to 1000 μm, preferably 50 μm to about 800 μm, although outer granules in this range can also be used. Inclusion of excipients as described above provides improved wetting, disintegration, dispersion and dissolution characteristics.

  In another embodiment, the CETP inhibitor composition comprises an amorphous solid dispersion coated with a protective coating. This coating is not acidic and substantially separates the amorphous solid dispersion from the HMG-CoA reductase inhibitor. The coating material is preferably water-soluble or dispersible in the environment of use. Examples of coating materials include sugars such as glucose, sucrose, xylitol, fructose, lactose, mannitol, sorbitol, and maltitol; cellulosic polymers such as ethylcellulose, methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, and hydroxypropylmethylcellulose; Cellulosic polymers such as polyethylene glycol, polyethylene oxide, polypropylene glycol, polyethylene-polypropylene glycol copolymer (polyoxamer), polyvinylpyrrolidone, starch, dextran, dextrin, polydextrose, polyalkene, polyether, polyvinyl alcohol, polyvinyl halide, polyvinyl Ethers; waxes, eg synthetic waxes, microcrystalline waxes , Paraffin wax, carnauba wax, and beeswax; and glycerides such as glyceryl monooleate, glyceryl monostearate, glyceryl palmitostearate, polyethoxylated castor oil derivatives, glyceryl mono-, di- and tribehenate, Contains hydrogenated vegetable oil, glyceryl tripalmitate, glyceryl tristearate. Mixtures of coating materials may be used. Preferred coating materials are cellulosic polymers such as hydroxyl ethyl cellulose, hydroxypropyl cellulose, and hydroxypropyl methyl cellulose; non-cellulose polymers such as polyethylene glycol, polyethylene oxide, poloxamer, and polyvinyl pyrrolidone; and mixtures thereof.

  The amorphous solid dispersion may be coated using methods known in the art, including solution coating and hot-melt coating processes. In a solution coating process, coating is performed by first forming a solution or suspension containing a coating excipient, a liquid (eg, a solvent), and optional coating additives. The coating material is either completely dissolved in the liquid or simply dispersed in the liquid, either as an emulsion or suspension or somewhere in between. Latex dispersions are an example of an emulsion or suspension that may be useful as a coating solution. The liquid used for this solution is inert in the sense that it does not react or decompose with the drug and is pharmaceutically acceptable. Preferably the liquid is volatile. “Volatile” means that the material has a boiling point of less than about 150 ° C. at ambient pressure, but a small amount of liquid with a higher boiling point can be used and still acceptable results are obtained. .

  Examples of liquids suitable for use in coating amorphous solid dispersions are alcohols such as methanol, ethanol, propanol isomers and butanol isomers; ketones such as acetone, methyl ethyl ketone and methyl isobutyl ketone; hydrocarbons such as Pentane, hexane, heptane, cyclohexane, methylcyclohexane, octane and mineral oil; ethers such as methyl tert-butyl ether, ethyl ether and ethylene glycol monoethyl ether; chlorocarbons such as chloroform, methylene dichloride and ethylene dichloride; tetrahydrofuran; dimethyl sulfoxide N-methylpyrrolidone; acetonitrile; water; and mixtures thereof.

  Coating formulations often include additives to facilitate application of the coating or to improve durability or stability. The coating additive used is preferably not acidic. Examples of coating additives are plasticizers such as mineral oil, petrolatum, lanolin alcohol, polyethylene glycol, polypropylene glycol, sorbitol and triethanolamine; pore increasing agents such as polyethylene glycol, polyvinylpyrrolidone, polyethylene oxide; hydroxyethylcellulose and hydroxypropylmethylcellulose And glidants such as colloidal silicon dioxide, talc and corn starch.

  Coatings include, for example, fluid bed coaters (e.g., Wurster coaters or surface-spray coaters available from Glatt Air Technologies (Ramsey, NJ) and Niro Pharma Systems (Bubendorf, Switzerland)) and rotary granulators (e.g., It may be formed on an amorphous solid dispersion by contacting the dispersion with a coating formulation using standard coating equipment such as CF-Granulator available from Freund. In some cases, the amorphous solid dispersion is granulated prior to coating with a non-acidic coating.

  In one method, a Wurster fluidized bed system is used. In this system, a cylindrical partition (Wurster column) is placed inside a conical product container in the apparatus. The air passes through a dispersion plate located at the bottom of the product container, fluidizes the amorphous solid dispersion, and most of the air moving upward passes through the Wurster column. Amorphous solid dispersion particles are drawn into a Wurster column equipped with an atomizing nozzle that sprays the coating formulation upward. The amorphous solid dispersion particles are coated while passing through the Wurster column, and this liquid is removed as the dispersion particles exit the column.

  Alternatively, a surface-spray method can be used to apply the coating. In this method, the coating formulation is sprayed onto the fluidized dispersion particles. The liquid evaporates from the coated dispersion particles, and the coated dispersion particles are fluidized again in the apparatus. The coating continues until the desired coating thickness is achieved. In general, preferred coatings are at least 1 μm thick, preferably at least 5 μm thick, more preferably at least 10 μm thick.

  In another method, using wet-granulation techniques, the coating is applied to an amorphous solid dispersion. In this method, the coating material is first dissolved or suspended in the granulating liquid. This granulation mixture is sprayed onto or mixed with the amorphous solid dispersion, resulting in a thin layer of coating material on the outer surface of the resulting granules. In the subsequent drying step, the granulating liquid is removed.

  The coating may be applied using hot-melt coating techniques. In this method, the coating excipients and additives are first melted and then sprayed onto the dispersion particles. Typically, a hot-melt coating is applied in a fluidized bed attached to a surface-spray collector.

  Another hot-melt coating application method to amorphous solid dispersion particles is the use of an improved melt-solidification method. This method suspends the dispersion particles in the molten coating excipient and makes the melting point of the dispersion higher than the melting point of the coating excipient. This suspension is then formed into droplets containing dispersion particles substantially surrounded by the coating excipient. These droplets are typically formed by an atomizer such as a rotary or spin-disk atomizer. The droplets are then cooled to solidify the coating excipient and form a coated dispersion.

  The coating may be applied in a rotary granulator. In such an apparatus, the horizontal disk rotates at high speed, forming a “rope” on which the dispersion particles rotate on the vessel wall. The rope is sprayed with a coating to coat the amorphous solid dispersion. This technique can be used with hot-melt and liquid-based coating solutions.

  The HMG-CoA reductase inhibitor composition contains an HMG-CoA reductase inhibitor and any excipients depending on the dosage form to be prepared. The amount of HMG-CoA reductase inhibitor can be varied according to the desired dosage of HMG-CoA reductase inhibitor. Preferably, the HMG-CoA reductase inhibitor is a crystal. The HMG-CoA reductase composition not only stabilizes the HMG-CoA reductase inhibitor from degradation due to the presence of acidic materials in the dosage form or processing environment, but also stores the HMG-CoA reductase inhibitor during storage. It is preferred to protect against photochemical degradation of.

  In a preferred embodiment, the HMG-CoA reductase inhibitor composition contains a stabilizer. This stabilizer stabilizes the HMG-CoA reductase inhibitor by reducing acid-catalyzed degradation. The stabilizer may be a basic inorganic pharmaceutically acceptable salt. Examples of salts include: calcium salts such as calcium carbonate and calcium hydroxide; magnesium salts such as magnesium carbonate, magnesium hydroxide, magnesium oxide, magnesium silicate, magnesium aluminate, and aluminum magnesium hydroxide; Salts of lithium, such as lithium hydroxide, and similar lithium compounds; or other suitable alkaline earth metal salts. The basic inorganic salt of calcium, lithium, or magnesium can be used in a mass ratio of about 0.1 to 1 and about 50 to 1 with respect to the active ingredient of the salt compound.

  A preferred stabilizer is calcium carbonate. The inventors have observed that the size of calcium carbonate particles correlates with the effectiveness of calcium carbonate as a stabilizer, and that smaller particle sizes produce better performance as a stabilizer. A preferred calcium carbonate grade is a precipitation grade of calcium carbonate having a particle size of less than about 10 μm. Examples of grades of precipitated calcium carbonate are Vicality Medium PCC and Vicality Heavy PCC available from Specialty Minerals, Pre-carb 15 available from Mutchler, and PCC-250 available from Particle Dynamics.

  The HMG-CoA reductase composition includes additional additives known as suitable substances in the art, including combinations and concentrations described in more detail below, in addition to the stabilizing metal salt or alkaline earth metal salt. A dosage form may also be included. In a preferred embodiment, the HMG-CoA reductase composition contains additional materials suitable for normal tablet formation. Such excipients include diluents, binders and disintegrants. Antioxidants can also be incorporated into the HMG-CoA reductase inhibitor composition to prevent oxidation of the drug compound. For example, antioxidants that can be used are butylated hydroxyanisole, sodium ascorbate, butylated hydroxytoluene, sodium metabisulfite, malic acid, citric acid and ascorbic acid.

  In one HMG-CoA reductase inhibitor composition, the composition contains a stabilizer, a diluent, a disintegrant and a surfactant. Calcium carbonate, a basic excipient, has been shown to chemically stabilize HMG-CoA reductase inhibitors, such as atorvastatin calcium. Microcrystalline cellulose and hydrous lactose are used as suitable diluents. Internally cross-linked carmellose sodium is present as a disintegrant. Tween 80, a non-ionic detergent, is used as a surfactant. The composition also includes hydroxypropylcellulose as a binder selected from several applicable materials such as polyethylene glycol, polyvinylpyrrolidone, polyvinyl alcohol, hydroxymethylcellulose or hydroxypropylmethylcellulose. As an antioxidant, reagents such as butylated hydroxyanisole, sodium ascorbate, or others may optionally be incorporated into the composition. Magnesium stearate may be selected from the group consisting of other materials such as stearic acid, palmitic acid, talc or similar lubricant compounds.

  Other possible auxiliary ingredients known to those of ordinary skill in the art, such as preservatives, desiccants, glidants, or colorants, optionally, HMG-CoA reductase inhibitor composition May be included.

  In one aspect, the HMG-CoA reductase inhibitor composition comprises the following components in a concentration range expressed by mass: HMG-CoA reductase inhibitor from about 1% to about 50%; calcium carbonate from about 5% to About 75%; about 5% to about 75% microcrystalline cellulose; about 1% to about 80% hydrous lactose; about 1% to about 15% internally crosslinked carmellose sodium; about 0.5% to about 6% hydroxypropylcellulose; Tween 80 from about 0.1% to about 4%; magnesium stearate from about 0.25% to about 2%; and sodium ascorbate from about 0.0% to about 3%.

  A more preferred HMG-CoA reductase inhibitor composition comprises appropriate concentrations expressed in terms of the mass of the following components: HMG-CoA reductase inhibitor, atorvastatin hemi-calcium trihydrate about 13.9 wt%; calcium carbonate About 42.4 wt%; about 17.7 wt% microcrystalline cellulose; about 19.2 wt% ungelatinized starch; about 2.5 wt% hydroxypropylcellulose; and about 0.5 wt% Tween 80.

  The HMG-CoA reductase inhibitor composition can be formed by any conventional method for combining HMG-CoA reductase inhibitors and excipients. Illustrative methods include wet and dry granulation. When wet granulation is used, a stabilizer such as calcium carbonate is preferably included to maintain chemical degradation of the HMG-CoA reductase inhibitor at an acceptable level.

  One exemplary method of forming an HMG-CoA reductase inhibitor composition is (a) crushing excess drug, (b) dissolving at least one binder additive in an aqueous surfactant solution. Step: (c) in a rotating mixing vessel equipped with a chopper device, at least one diluent additive with crushed drug and at least one drug-stabilizing additive, and drug-stabilizing additive And (d) blending with half of the disintegrant additive; (d) mixing the drug ingredient mixture formulated in step (c) with increasing amounts of the surfactant / binder solution of step (b) Granulating in an equipped mixing vessel; (e) drying the granulated drug mixture overnight at about 50 ° C .; (f) sieving the dried granulated drug mixture; (g) Tumble blending the sieved drug mixture with the remaining amount of disintegrant additive; (h) Extent Aliquots of drug mixtures (g), were mixed separately with magnesium stearate, which was sieved, and returns it to the drug mixture of (g), comprising the step of tumble blended drug mixture total.

  In another embodiment, the HMG-CoA reductase inhibitor composition contains an HMG-CoA reductase inhibitor coated with a protective coating. In this embodiment, the HMG-CoA reductase inhibitor crystals or granules containing the HMG-CoA reductase inhibitor and optional excipients are coated with a protective coating. The same protective coating and coating method as described above for applying the protective coating to the amorphous solid dispersion may be used to coat the HMG-CoA reductase inhibitor.

  The unit dosage form is an HMG-CoA reductase inhibitor composition of a CETP inhibitor composition such that the amorphous solid dispersion and the HMG-CoA reductase inhibitor are substantially separated in the dosage form. And a combination.

  In one embodiment, the CETP inhibitor composition and the HMG-CoA reductase inhibitor composition are formulated together and then compressed to form a dosage form, such as a tablet, caplet, or pill. Virtually any process can be used to formulate the composition, provided that the amorphous solid dispersion and the HMG-CoA reductase inhibitor remain substantially separated in the dosage form. For example, these compositions can be formulated in rotating shell mixers, fixed-shell mixers, planetary paddle mixers, and twin-shell mixers, all of which are known in the art.

  Compressed dosage forms can be formed using a wide variety of molding machines used for secondary processing of pharmaceutical dosage forms. Examples are single shot punching machines, rotary tablet presses, and multi-layer rotary tablet presses, all well known in the art. See "Remington's Pharmaceutical Sciences" (18th edition, 1990). The compressed dosage form can be any shape including circular, elliptical, cylindrical, or triangular. The upper and lower surfaces of the compressed dosage form may be flat, rounded, concave, or convex.

When formed by compression, the dosage form is preferably at least 5 kiloponds (Kp) / cm ^2, more preferably "strength" of at least 7 Kp / cm ^2. Here, “strength” is the breaking force required to break a tablet formed from a material divided by the maximum cross-sectional area of the tablet normal to that force, also known as tablet “hardness”. The breaking force can be measured using a Sherlogger tablet hardness tester model 6D. In order to achieve the desired strength, the CETP inhibitor composition and the HMG-CoA reductase inhibitor composition formulation is compressed with sufficient force in forming the dosage form while the amorphous solid dispersion It should be ensured that the body and the HMG-CoA reductase inhibitor remain substantially separated in the dosage form. The compressive force required to achieve this strength depends on the size of the dosage form, but will generally be greater than about 5 kP / cm ² . Friction is a measure of the resistance to surface friction of a well-known dosage form, which measures the percent lost weight after subjecting the dosage form to standard agitation techniques. A value of 0.8 to 1.0% friability is considered to constitute an acceptable upper limit. Dosage forms having a strength greater than 5 kP / cm ² are generally very robust and have a friability of less than 0.5%, preferably less than 0.1%.

  In some embodiments, the unit dosage form also includes a separation layer that physically separates the CETP inhibitor composition from the HMG-CoA reductase inhibitor composition. The separating layer is preferably not acidic. Examples of materials suitable for use in the separation layer include those listed above as suitable for use in forming a protective coating around the amorphous solid dispersion.

  In one embodiment, the unit dosage form is a CETP inhibitor and acidic concentrate mixed with a second granule containing an HMG-CoA reductase inhibitor, schematically shown in dosage form 50 of FIG. A first granule containing an amorphous solid dispersion of a polymerized polymer. Here, CETP inhibitor granule 52 is mixed with HMG-CoA reductase inhibitor granule 54 and then compressed into a unit dosage form.

  The following process can be used to form a compressed unit dosage form. First, granules of a CETP inhibitor composition are prepared. For example, in a concentrated polymer such as hydroxypropylmethylcellulose succinate (HPMCAS), about 25 wt% of the CETP inhibitor [2R, 4S] 4-[(3,5-bis-trifluoromethyl-benzyl) -methoxycarbonyl- Amorphous solid dispersions containing amino] -2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester can be prepared by a spray drying process. Next, about 60.15 wt% amorphous solid dispersion, about 14.79 wt% microcrystalline cellulose, and about 10.03 wt% internally crosslinked povidone can be blended, for example, in a twin-shell blender for 15 minutes. Next, about 0.25 wt% magnesium stearate is added and the mixture is blended for an additional 5 minutes. This blend is then densified using a rotary compressor. The size of the compact is then reduced by grinding. Next, about 14.78 wt% anhydrous dibasic calcium phosphate is added and blended in a twin-shell blender for 5 minutes to form granules of a CETP inhibitor composition having an average particle size of about 140 μm.

  Next, granules of the HMG-CoA reductase inhibitor composition are prepared. For example, an HMG-CoA reductase inhibitor, atorvastatin hemi-calcium trihydrate, about 13.9 wt%; calcium carbonate, about 42.4 wt%; microcrystalline cellulose, about 17.7 wt%; and ungelatinized starch, about 19.2 wt% It can be fluidized in a fluid bed granulator. An aqueous solution containing about 2.5 wt% hydroxypropylcellulose and about 0.5 wt% Tween 80 is sprayed onto the floor to form granules. The granules are then dried on the floor and the granulating water is removed. The granule size is then reduced by grinding to form granules with an average granule size of about 110 μm.

Formation of unit dosage form containing CETP inhibitor 60mgA and HMG-CoA reductase inhibitor 40mgA is formulated with CETP inhibitor granule 399mg and HMG-CoA reductase inhibitor granule 313mg in twin-shell blender for 10 minutes . Next, 1.8 mg of lubricant magnesium stearate is added to the mixture and blended for an additional 5 minutes. A compressed tablet containing 713.78 mg of material is then formed using a modified ellipsoid mold of 0.3301-inch (0.8385 cm) × 0.6603-inch (1.6772 cm). A compression of 20 kN yields tablets with a hardness of 8.2 kP. Based on a tablet cross-sectional area of 1.1 cm ² , this corresponds to a tablet strength of 7.5 kP / cm ² .

  Alternatively, a mixture of the two compositions described above can be filled into capsules such as hard- or soft-gelatin capsules or other materials such as capsules made from starch to form unit dosage forms. May be.

  In another embodiment, the unit dosage form may be formed by the following process. First, the HMG-CoA reductase inhibitor is mixed with excipients and granulated using dry- or wet-granulation techniques to form granules of the HMG-CoA reductase inhibitor composition. The HMG-CoA reductase inhibitor composition granules are then granulated using an amorphous solid dispersion containing a CETP inhibitor and an acidic concentrated polymer and optional excipients and dry- or wet-granulation techniques. Mixed with the resulting mixture. The resulting granules containing HMG-CoA reductase inhibitor composition and CETP inhibitor composition are then compressed into tablets, caplets or pills, or these granules are hard- or soft, for example. -Filled into capsules such as gelatin capsules.

  In another embodiment, the unit dosage form may be formed by the following process. First, an amorphous solid dispersion containing a CETP inhibitor and an acidic concentrated polymer is mixed with any excipient and granulated using dry- or wet-granulation techniques to produce a CETP inhibitor composition Form granules. The CETP inhibitor composition granules can then be mixed with the resulting mixture granulated using a HMG-CoA reductase inhibitor and any excipients and dry- or wet-granulation techniques. The resulting granules containing the HMG-CoA reductase inhibitor composition and CETP inhibitor composition are then compressed into tablets, caplets or pills, or these granules are hard- or soft, for example. -Filled into capsules such as gelatin capsules.

  In another embodiment, the unit dosage form may be formed by the following process. First, the HMG-CoA reductase inhibitor composition is compressed into tablets, caplets, or pills. The resulting compressed tablet, caplet, or pill is then encapsulated with the CETP inhibitor composition. Alternatively, the CETP inhibitor composition is first compressed into tablets, caplets, or pills. The resulting compressed tablet, caplet, or pill is then encapsulated with the HMG-CoA reductase inhibitor composition.

  In another embodiment, the unit dosage form may be formed by the following process. First, the HMG-CoA reductase inhibitor composition is a multi-granule using processes well known in the art such as, for example, extrusion spheronization, cold pelletization, spray drying, or melt-solidification. A multiparticulate is formed. See, for example, “Remington: The Science and Practice of Pharmacy” 20th edition (2000). The resulting multi-granule is then placed in a capsule with a CETP inhibitor composition. Alternatively, the CETP inhibitor composition is first formed into a multi-granule and placed in a capsule with the HMG-CoA reductase inhibitor composition. In another method, the HMG-CoA reductase inhibitor composition is formed into a multi-granule and the CETP inhibitor composition is formed into a multi-granule, which are then mixed and placed in a capsule.

  In another embodiment, the unit dosage form is in the form of a kit. The kit includes two separate compositions: (1) including an amorphous solid dispersion containing a CETP inhibitor and an acidic concentrated polymer, and (2) including an HMG-CoA reductase inhibitor. thing. The kit is designed such that the HMG-CoA reductase inhibitor and the amorphous solid dispersion are substantially separated. The kit comprises means comprising a separated composition, for example a container such as a divided bottle, pouch, box, bag or other container known in the art, or a divided foil parcel; The resulting composition may be contained in a single undivided container. An example of this type of kit is a blister pack, where each individual blister contains two (or more) tablets and one (or more) tablet (s) is CETP-inhibited. The drug composition is contained and the second (or subsequent) tablet (s) contain the HMG-CoA reductase inhibitor composition. In one embodiment, the HMG-CoA reductase inhibitor composition is in the form of a compressed tablet. In another embodiment, the CETP inhibitor composition is in the form of a compressed tablet. In another embodiment, the HMG-CoA reductase inhibitor composition is in the form of a multigranulate. In another embodiment, the CETP inhibitor composition is in the form of a multigranulate. Typically, the kit includes instructions for administration of the separated components.

  Thus, in one embodiment, the unit dosage form constitutes a kit comprising (1) a therapeutically effective amount of a CETP inhibitor in a CETP inhibitor composition; (2) HMG-CoA reductase inhibition A therapeutically effective amount of an HMG-CoA reductase inhibitor in the pharmaceutical composition; and (3) a container containing a CETP inhibitor composition and an HMG-CoA reductase inhibitor composition.

  An example of such a kit is a so-called blister pack, as implied above. Blister packs are well known in the packaging industry and are widely used for packaging pharmaceutical unit dosage forms such as tablets, capsules and the like. Blister packs generally consist of a sheet of relatively hard material, preferably covered with a foil of transparent plastic material. During the packaging process, depressions are formed in the plastic foil. The depression has a size and shape such that a tablet or capsule can be packaged. The tablets or capsules are then placed in the depressions, and a sheet of relatively hard material is sealed against the plastic foil with a foil surface that is opposite to the direction in which the depressions were formed. As a result, the tablets or capsules are sealed in the recesses between the plastic foil and the sheet. Preferably, the strength of the sheet is such that with the pressure of the hand applied to the recess, an opening is formed in the sheet at the location of the recess and the tablet or capsule is removed from the blister pack. The tablet (s) or capsule (s) can then be removed from this opening.

  The kit is provided with a memory aid, such as, for example, the shape of the number next to the tablet or capsule corresponding to the number of days of medication that the specified tablet or capsule must be taken. It may be desirable to provide. Another example of such a memory aid symbol is a calendar printed on a card such as “first week, Monday, Tuesday,..., Second week, Monday, Tuesday,. is there. Other variations of memory assist symbols will be readily apparent.

<Coating>
The unit dosage form may optionally be coated with conventional coatings well known in the art. The coating can also be used to mask the taste of the dosage form, improve its appearance, promote swallowing, or delay, sustain or control the release of the drug from the dosage form. Such coatings can be fabricated by conventional means including fluidized bed coating, spray-coating, pan-coating and powder-coating using aqueous or organic solvents. Examples of suitable coating materials are sucrose, maltitol, cellulose acetate, ethylcellulose, methylcellulose, sodium carboxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose; polymethacrylate, polyacrylate, polyvinyl alcohol, polyvinylpyrrolidone, cetyl alcohol , Gelatin, maltodextrin, paraffin wax, microcrystalline wax, and carnauba wax. Polymer mixtures can also be used. Preferred coatings are commercially available aqueous coating formulations, Surelease ™ and Opadry ™, available from Colorcon (West Point, PA).

  In some cases, it is desirable that the drug in the unit dosage form not be released in the stomach in order to avoid intolerance or avoid degradation. In such cases, the dosage form is one or more pH-sensitive coatings, commonly referred to in the pharmaceutical field as “enteric” coatings, by the usual technique of delaying drug release until reaching the duodenum or small intestine. You may coat | cover with a composition. PH-sensitive polymers suitable for enteric coatings are those that are relatively insoluble and not impregnated at gastric pH, but more likely, disintegratable or impregnable at duodenal or small intestinal pH. Including. Such pH-sensitive polymers include polyacrylamide, phthalic acid derivatives such as phthalates of carbohydrates, amylose acetate phthalate, cellulose acetate phthalate (CAP), other phthalate cellulose esters, cellulose phthalate ether, phthalate Hydroxypropylcellulose (HPCP), Hydroxypropylethylcellulose phthalate (HPECP), Hydroxypropylmethylcellulose phthalate (HPMCP), HPMCAS, Methylcellulose phthalate (MCP), Polyvinyl acetate phthalate (PVAcP), Polyvinyl acetate hydrogenated phthalate, Sodium CAP, acid phthalate carbohydrate, cellulose acetate trimellitic acid (CAT), styrene-maleic acid dibutyl phthalate copolymer, styrene-maleic acid / polyvinyl acetate phthalate copolymer, styrene and maleic acid copolymer , Polyacrylic acid derivatives, for example acrylic acids and esters of acrylic acid copolymers, polymethacrylic acid and esters thereof, polyacrylic acid and methacrylic acid copolymers, copolymers of shellac and vinyl acetate and crotonic acid.

  A preferred group of pH-sensitive polymers are CAP, PVAcP, HPMCP, HPMCAS, anionic acrylic acid copolymers of methacrylic acid and methyl methacrylate, and copolymers of acrylic acid and at least one acrylic ester.

  For application of this pH-sensitive coating to a dosage form, the pH-sensitive polymer is first dissolved or suspended in a suitable solvent to form a coating solution. Solvents useful for this purpose are ketones such as acetone; alcohols such as methanol, ethanol, isopropyl alcohol, n-propyl alcohol, and butanol isomers; chlorinated hydrocarbons such as methylene chloride; water And mixtures of these solvents. The polymer may be suspended in a solvent. The coating solution can also include a latex of a pH-sensitive polymer suspended in an aqueous solution.

  The coating solution may also contain one or more plasticizers such as, for example, polyethylene glycol, triethyl citrate, propylene glycol, diethyl phthalate, dibutyl phthalate, castor oil, triacetin and others known in the art. . The coating solution can also include one or more emulsifiers, such as polysorbate-80. Coating is done in the usual manner, typically by dipping, spray-coating, or pan-coating.

  The coating solution may contain a base or buffer, such as those discussed above. The use of a base or buffer will ensure that the pH of the coating solution is not so low as to increase the chemical degradation of the HMG-CoA reductase inhibitor. The use of a base or buffer can also be used to minimize reaction of the coating formulation with other excipients in the dosage form.

  CETP inhibitors and HMG-CoA reductase inhibitors using unit dosage forms of the present invention, such as disclosed in co-pending application US 2002 / 0035125A1, assigned to the assignee of the present invention Can be used to treat any condition that is treated. This disclosure is incorporated herein by reference.

In one aspect, the unit dosage form of the present invention is used for the treatment of anti-atherosclerosis.
In another aspect, the unit dosage forms of the present invention are used to slow and / or stop the progression of atheromatous plaques.
In another aspect, the unit dosage form of the present invention is used to delay the progression of atheromatous plaque in the coronary arteries.
In another aspect, the unit dosage form of the present invention is used to delay the progression of atheromatous plaque in the carotid artery.

In another aspect, the unit dosage form of the present invention is used to delay the progression of atheromatous plaque of the peripheral arterial system.
In another aspect, the unit dosage form of the present invention causes regression of atherosclerosis when used in the treatment of atherosclerosis.
In another aspect, the unit dosage form of the present invention is used for retraction of atheromatous plaques in the coronary arteries.
In another aspect, the unit dosage form of the present invention is used for retraction of atheromatous plaques in the carotid artery.
In another aspect, the unit dosage form of the present invention is used for retraction of atheromatous plaques of the peripheral arterial system.

In another aspect, the unit dosage forms of the invention are used for the treatment of elevated HDL and the treatment of antihyperlipidemia (including a reduction in LDL).
In another aspect, the unit dosage form of the present invention is used for the treatment of antianginal.
In another aspect, the unit dosage form of the present invention is used for cardiac risk management.

  Other features and embodiments of the present invention will become apparent from the following examples, which are provided for purposes of illustration and not to limit the intended scope of the invention.

Example 1
Granules of atorvastatin, an HMG-CoA reductase inhibitor, and granules of an amorphous solid dispersion containing a CETP inhibitor and a concentrated polymer were each formed individually. These two granules were combined and stored for 3 weeks at 50 ° C. and 75% relative humidity. The stability of atorvastatin was measured and found to be improved relative to the control composition.

Using the following process, [2R, 4S] -4-[(3,5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -2-ethyl-6-trifluoromethyl-3,4-dihydro -2H-quinoline-1-carboxylic acid ethyl ester (torcetrapib) 25wt% and hydroxypropylmethylcellulose succinate 75wt% (moderate granule grade available from Shin Etsu, Japan) (here "HPMCAS-MG" A spray-dried dispersion was formed. Initially, a spray solution was formed containing 25 g torcetrapib, 75 g HPMCAS-MG, and 900 g acetone. This spray solution is spray-dried (liquid-feed material) equipped with a pressurized atomizer (Spraying Systems Pressure nozzle and Body (SK 79-16)) using a high-pressure pump (Zenith Z-Drive 2000 High-Pressure Gear Pump). Pumped to Niro type XP portable spray-dryer equipped with processing vessel [PSD-1]. PSD-1 was fitted with a 9-inch chamber extension. The spray dryer was also equipped with a diffusion plate with 1% free space. The nozzle was flushed with a diffusion plate during operation. The spray solution was pumped to the spray dryer at about 185 gm / min and atomizer pressure of about 280 psi. Dry gas (nitrogen) was circulated through the diffusion plate at an inlet temperature of about 98 ° C. The evaporated solvent and wet drying gas were discharged from the spray dryer at a temperature of 31 ± 4 ° C. The spray-dried dispersion formed by this process was collected in Cyclo®, which had a bulk specific volume of about 5 cm ³ / g. The amorphous solid dispersion was post-dried using a Gruenberg one-pass convection shelf dryer, operating at 40 ° C. for about 16 hours.

  The spray-dried amorphous solid dispersion was evaluated in an in vitro dissolution test using microcentrifugation. In this test, 7.2 mg of spray-dried amorphous solid dispersion was placed in a microcentrifuge tube. Place this tube in a sonication bath at 37 ° C, add 1.8 mL phosphate buffered saline (PBS) pH 6.5 and 290 mOsm / kg, and if all of the drug is dissolved, the torcetrapib concentration 1000 μg / mL Produced. This sample was rapidly mixed using a vortex mixer for about 60 seconds. Samples were centrifuged at 13,000 G for 1 minute at 37 ° C. The resulting supernatant solution was then collected, diluted with methanol to 1: 6 (by volume), and then analyzed by high performance liquid chromatography (HPLC). The contents of the tube were mixed on a vortex mixer and allowed to stand at 37 ° C. until the next sample was taken. Samples were collected at 4, 10, 20, 40, 90 and 1200 minutes. The concentration of drug obtained in these samples is shown in Table 1, which represents the average of duplicate tests.

  As a control, an in vitro dissolution test was performed using the procedure described above, except that 1.8 mg of crystalline drug was used. The drug concentrations obtained in the in vitro dissolution test are shown in Table 1.

The results of these dissolution tests are summarized in Table 2, which shows the maximum concentration of torcetrapib in solution during the first 90 minutes of the test (MDC ₉₀ ), the area under the aqueous concentration versus time curve after 90 minutes (AUC ₉₀ ), and 1200 The concentration in minutes (C ₁₂₀₀ ) is shown.

The results summarized in Table 2 indicate that the amorphous solid dispersion resulted in increased concentrations relative to the crystalline drug. The amorphous solid dispersion provided 805-fold greater C _max90 value than the crystalline drug and 756-fold greater AUC ₉₀ value than the crystalline drug.

  Granules of the torcetrapib dispersion were prepared with the following composition: amorphous solid dispersion 60 wt%; microcrystalline cellulose (Avicel PH105, obtained from FMC (Philadelphia, PA)) 14.8 wt%; internally crosslinked povidone (Polyplasmidone, obtained from International Specialty Products, Wayne, NJ) 10.0 wt%; dibasic calcium phosphate (A-Tab, obtained from Rodia (Cranbury, NJ)) 14.8 wt%; and magnesium stearate 0.5 wt%. First, an amorphous solid dispersion, microcrystalline cellulose, and internally cross-linked povidone were added to an 8-quart twin shell blender and blended for 15 minutes. Half of the magnesium stearate was added and the mixture was blended for 5 minutes. The mixture was roller-compressed using a TF-mini roller compressor at a roller pressure of 450 psi, a roller speed of 4 rpm, an auger speed of 25 rpm, and a target ribbon thickness of 0.07 to 0.08-inch. The mixture was then ground using a M5A mill with a 0.033 inch Conidur screen, 500 rpm, with a knife head. The granules were then added to an 8-quart twin shell blender and blended for 15 minutes. Dicalcium phosphate was added and the mixture was blended for 15 minutes. Half of the remaining magnesium stearate was added and the mixture was blended for 5 minutes. The resulting granules formed a CETP inhibitor composition.

  Atorvastatin calcium granules were made using the following process. Granules: atorvastatin hemi-calcium salt trihydrate 13.9 wt%, calcium carbonate (Pre-carb 150, obtained from Mutchler, Westwood, NJ) 42.4 wt%, microcrystalline cellulose (Avicel PH 101, FMC) 17.7 wt%, internally crosslinked carmellose sodium (AcDiSol, FMC) 3.8wt%, polysorbate 80 (Crillet 4HP, Croda, Parsippany, NJ) 0.5wt%, hydroxypropylcellulose (Klucel EF, Hercules, Wilmington, DE) 2.6 and 19.2 wt% ungelatinized starch (Starch 1500, obtained from Colorcon, West Point, PA). To form the granules, atorvastatin calcium, calcium carbonate, microcrystalline cellulose, and starch were loaded into a fluid bed granulator. A granulating liquid containing polysorbate 80 and hydroxypropyl cellulose dissolved in water was sprayed onto the fluidized material to form granules. The weight of water used is equal to half the weight of the granules. The granules were then dried using air with an inlet temperature of about 45 ° C. in a fluidized bed until less than 2% water of the final point on drying was achieved. The granules were then milled using a Fitzpatrick M5A mill. The mill was equipped with a ~ 0.03-inch rasping plate and a wand and operated at about 500 rpm in the direction of the knife (counterclockwise). The average particle size of the granules was about 105 μm using sieve analysis. This composition contained an HMG-CoA reductase inhibitor composition.

  To form Example 1, 86 wt% CETP inhibitor composition and 14 wt% HMG-CoA reductase inhibitor composition were mixed together, screened and mixed again in a twin shell blender. It was then compressed into small chunks. The small mass was then crushed using a pestle and mortar. The acidic concentrated polymer HPMCAS comprised 38.7 wt% of Example 1, atorvastatin calcium comprised 1.96 wt% of Example 1, and the HPMCAS / atorvastatin ratio was 19.7 (w / w).

  Control 1 consists of a mixture of crystalline atorvastatin calcium (2 wt%) and CETP inhibitor amorphous solid dispersion (98 wt%). Crystalline atorvastatin calcium and an amorphous solid dispersion were mixed together in a Turbula mixer, sieved, mixed again, and then compressed into a blob. The small mass was then crushed using a pestle and mortar. The acidic concentrated polymer HPMCAS comprised 73.5 wt% of Control 1, atorvastatin calcium comprised 2 wt% of Control 1, and the HPMCAS / atorvastatin ratio was 36.8 (w / w).

  Control 2 consists of crystalline atorvastatin calcium (1.42 wt%) and CETP inhibitor dispersion (62.05 wt%), and all excipients used for both granulations (calcium carbonate-4.32 wt%, internally cross-linked carmellose sodium -0.39wt%, microcrystalline cellulose-3.07wt%, ungelatinized starch-1.95, polysorbate 80-0.05wt%, hydroxypropylcellulose-0.26, internally crosslinked povidone-10.42, magnesium stearate-0.26, calcium phosphate-15.36wt %). These materials were mixed together in a Turbula mixer, sieved, mixed again, and then compressed into a blob. The small mass was then crushed using a pestle and mortar. The acidic concentrated polymer HPMCAS comprised 46.9 wt% of Control 2, atorvastatin calcium comprised 1.42 wt% of Control 1, and the HPMCAS / atorvastatin ratio was 33.0 (w / w).

  To mimic the relatively long shelf life in a typical storage environment, Example 1 and Controls 1 and 2 were stored at 50 ° C. and 75% relative humidity for 3 weeks to determine the chemical and physical changes that occur in the material. Increased percentage.

  After storage, samples were analyzed for atorvastatin purity using HPLC. In order to analyze the sample by HPLC, a sample of the composition containing about 0.4 mgA atorvastatin was added to the dissolution solvent. The dissolving solvent was prepared by a combination of 150 mL of 50 mM ammonium acetate (pH 7.0), 600 mL of acetonitrile, and 250 mL of methanol. Mobile phase A was prepared by adding 3 mL of acetic acid to 530 mL of water, adjusting to pH 4.0 with ammonium hydroxide, and then adding 270 mL of acetonitrile and 200 mL of tetrahydrofuran. Mobile phase B was made by adding 1 mL of acetic acid to 100 mL of water, adding half of the amount of ammonium hydroxide used to adjust mobile phase A, followed by 700 mL of acetonitrile and 200 mL of tetrahydrofuran. Samples were analyzed using a Waters Spherisorb ODS2 column at a solvent flow rate of 1.5 mL / min. Table 3 shows the solvent gradient used.

  UV absorbance of atorvastatin and atorvastatin impurities was measured at a wavelength of 244 nm. The atorvastatin lactone impurity eluting after approximately 10.4 minutes was selected as the basis for comparison. All impurity peak areas were added and lactone impurities were calculated as% of the total peak area to obtain the degree of decomposition. The results are shown in Table 4.

  The results in Table 4 showed that atorvastatin in the sample of Control 1 (Atorvastatin mixed with CETP inhibitor amorphous solid dispersion) contained 1.55 wt% lactone impurity. Control 2 (a mixture containing crystalline atorvastatin, CETP inhibitor amorphous solid dispersion, and excipients used for both granulations) contained 2.66 wt% lactone impurity. Example 1 shows granulating atorvastatin with excipients, then granulating an amorphous solid dispersion with excipients, followed by mixing the two granulations, improved atorvastatin stability Showed that it provided. The relative improvement in chemical stability was determined by calculating the ratio between the degree of degradation of the drug in the control composition and the degree of degradation of the drug of Example 1. When compared to Control 1, Example 1 had a relative improvement of 9.12 (1.55 wt% / 0.17 wt%). When compared to Control 2, Example 1 had a relative improvement of 15.6.

Examples 2 and 3
The equivalent weights of the granulated CETP inhibitor composition of Example 1 and the granulated HMG-CoA reductase inhibitor composition of Example 1 were described in Example 1 to form Example 2. Formulated as above, 200 mg tablets were formed from this formulation. The acidic polymer HPMCAS comprised 22.5 wt% of Example 2, atorvastatin calcium comprised 6.95 wt% of Example 2, and the ratio of HPMCAS to atorvastatin was 3.24.

  To form Example 3, a tablet was prepared that contained separate layers of the CETP inhibitor composition of Example 1 and the HMG-CoA reductase inhibitor composition of Example 1. Each tablet of Example 3 contained 400 mg dispersion granulation in one layer and 288 mg atorvastatin granulation in the second layer. The acidic concentrated polymer HPMCAS comprised 26.2 wt% of Example 3, atorvastatin comprised 5.82 wt% of Example 3, and the ratio of HPMCAS to atorvastatin was 4.5.

  Examples 2 and 3 were stored at 50 ° C. and 75% relative humidity for 3 weeks and analyzed using HPLC as previously described. The results are shown in Table 5.

  Example 2 shows the formation of the first individual granules to form a tablet (one containing an amorphous solid dispersion and one containing atorvastatin), and then the tablet produced by blending the granules is It shows that a tablet with improved atorvastatin stability was provided. The relative improvement was 29.6 when comparing Example 2 to Control 2 (a mixture containing crystalline atorvastatin CETP inhibitor dispersion and excipients used for both granules). Example 3 showed that the tablets made by forming separate layers of amorphous solid dispersion granules and atorvastatin granules provided further improved atorvastatin stability. Compared to Control 2 in Example 3, the relative improvement was 66.5.

Examples 4 to 11
Unit dosage forms were prepared by the process described in Example 2 except as noted in Table 6. The properties of these tablets are shown in Table 7.

  Samples of the tablets of Examples 6, 7, 10 and 11 were stored at 40 ° C. and 75% RH for 6 weeks. Table 8 shows the concentration of lactone degradation in the tablet before and after storage, as well as the degree of degradation of atorvastatin calcium. These data indicate that tablet formation using the granulated composition results in a low degree of degradation of atorvastatin calcium.

Example 12
Granules of an amorphous solid dispersion containing the HMG-CoA reductase inhibitor atorvastatin and the CETP inhibitor and concentrated polymer were combined and stored for 6 weeks at 40 ° C. and 75% relative humidity. This composition showed chemical degradation of an acceptable amount of HMG-CoA reductase inhibitor.

  Spray-dried amorphous solid dispersion containing 40% by weight of torcetrapib and 60% by weight of hydroxypropylmethylcellulose succinate acetate (high granule grade obtained from Shin Etsu, Japan) (herein referred to as “HPMCAS-HG”) Was formed using a process similar to that described in Example 1 with the following exceptions. The spray solution contained 20 g of torcetrapib, 30 g of HPMCAS-HG, and 450 g of acetone. The spray solution was pumped to a PSD-1 spray dryer equipped with a pressurized atomizer (Spraying Systems Pressure Nozzzle and Body (SK 80-16)). PSD-1 was equipped with a 9-inch chamber extension. The spray dryer was also equipped with a diffusion plate with 1% free space. The spray solution was pumped to the spray dryer at about 145 gm / min and atomizer pressure of about 250 psi. Dry gas (nitrogen) was circulated through the diffusion plate at an inlet temperature of about 97 ° C. The evaporated solvent and wet drying gas were discharged from the spray dryer at a temperature of 46 ° C. The amorphous solid dispersion was post-dried using a Gruenberg one-pass convection shelf dryer, operating at 40 ° C. for about 16 hours.

  The spray-dried amorphous solid dispersion was evaluated in an in vitro dissolution test using microcentrifugation. In this test, 4.5 mg of spray-dried amorphous solid dispersion was placed in a microcentrifuge tube. Place this tube in a sonication bath at 37 ° C. and add 1.8 mL phosphate buffered saline (PBS) at pH 6.5 and 290 mOsm / kg and if all of the drug is dissolved, the torcetrapib concentration is 1000 μg / yielded mL. This sample was rapidly mixed using a vortex mixer for about 60 seconds. Samples were centrifuged at 13,000 G for 1 minute at 37 ° C. The resulting supernatant solution was then collected, diluted with methanol to 1: 6 (by volume), and then analyzed by high performance liquid chromatography (HPLC). The contents of the tube were mixed on a vortex mixer and allowed to stand at 37 ° C. until the next sample was taken. Samples were collected at 4, 10, 20, 40, 90 and 1200 minutes. The concentration of drug obtained in these samples is shown in Table 9, which is expressed as the average of duplicate tests. For comparison, the test results using crystalline drug are included in Table 9.

The results of these dissolution tests are summarized in Table 10, which shows the maximum concentration of torcetrapib in solution during the first 90 minutes of the test (MDC ₉₀ ), the area under the aqueous concentration versus time curve after 90 minutes (AUC ₉₀ ) , And a concentration of 1200 minutes (C ₁₂₀₀ ).

The results summarized in Table 10 indicate that the amorphous solid dispersion resulted in increased concentrations relative to the crystalline drug. The amorphous solid dispersion provided 79-fold greater C _max90 value than the crystalline drug and 21-fold greater AUC ₉₀ value than the crystalline drug.

  To form Example 12, 78 wt% CETP inhibitor amorphous solid dispersion of Example 1 and 22 wt% HMG-CoA reductase inhibitor composition were mixed together in a twin-shell blender and sieved Divided, mixed again and then compressed into small chunks. The acidic concentrated polymer HPMCAS-HG comprised 47 wt% of Example 12, atorvastatin calcium comprised 0.93 wt% of Example 12, and the HPMCAS-HG / atorvastatin ratio was 15 (w / w). It was.

  Example 12 was stored at 40 ° C. and 75% relative humidity for 6 weeks to mimic the relatively long storage period in a typical storage environment, increasing the rate of chemical and physical changes that occur in the material. After storage, samples were analyzed by HPLC for atorvastatin purity as shown in Example 1. The results are summarized in Table 11, which shows that this sample has a degree of degradation of 0.16 wt%, and the combination of HMG-CoA reductase inhibitor granules and amorphous solid dispersion has an acceptable low level of HMG. -It has been shown to cause degradation of CoA reductase inhibitors.

  The terms and expressions used in the foregoing specification are used as terms of description rather than limitation, and the use of such terms and expressions excludes equivalents of features presented and described, or parts thereof. It is not intended that the scope of the invention be defined and limited solely by the appended claims.

FIGS. 1-8 are schematic cross-sections of exemplary embodiments of dosage forms of the present invention.

Claims (15)

(a) a cholesteryl ester transfer protein inhibitor composition comprising an amorphous solid dispersion of a cholesteryl ester transfer protein inhibitor and an acidic concentrated polymer; and
(b) a unit dosage form containing an HMG-CoA reductase inhibitor composition containing an HMG-CoA reductase inhibitor;
Wherein said amorphous solid dispersion and said HMG-CoA reductase inhibitor are substantially separated from each other within said dosage form.   2. The unit dosage form of claim 1, wherein the dosage form comprises a number of granules of the cholesteryl ester transfer protein inhibitor composition and a number of granules of the HMG-CoA reductase inhibitor composition.   The dosage form includes at least two layers, at least one of the layers includes the cholesteryl ester transfer protein inhibitor composition, and the other of the layers includes the HMG-CoA reductase inhibitor composition. The unit dosage form of claim 1.   2. The unit dosage form of claim 1, wherein at least one of the cholesteryl ester transfer protein inhibitor composition and the HMG-CoA reductase inhibitor composition comprises a non-acidic coating.   The dosage forms include tablets, caplets, pills, capsules, powders, and one or more tablets, caplets, pills, capsules, sachets intended to be taken together 2. The unit dosage form of claim 1, wherein the unit dosage form is selected from the group consisting of: a kit comprising a powder or liquid. The dosage form is:
(a) an improvement in the maximum concentration of the cholesteryl ester transfer protein inhibitor in a use environment of at least 1.25 times compared to a control composition consisting essentially of the cholesteryl ester transfer protein inhibitor alone;
(b) at least 2-fold the control composition consisting essentially of the cholesteryl ester transfer protein inhibitor alone, between when introduced into the use environment and between about 270 minutes after introduction into the use environment. The area under the cholesteryl ester transfer protein inhibitor concentration versus time curve in the use environment for a period of at least 90 minutes;
(c) a maximum concentration of the cholesteryl ester transfer protein inhibitor in blood that is at least 1.25-fold relative to the control composition consisting essentially of the cholesteryl ester transfer protein inhibitor alone; and
(d) provide at least one improvement in the relative bioavailability of the cholesteryl ester transfer protein inhibitor in the environment of use that is at least 1.25-fold over the control composition consisting essentially of the cholesteryl ester transfer protein inhibitor alone The unit dosage form according to claim 1.   Compared to a control composition, wherein the composition consists essentially of a mixture of individual components of the cholesteryl ester transfer protein inhibitor composition and individual components of the HMG-CoA reductase inhibitor composition. 2. The unit dosage form of claim 1, which provides improved chemical stability of an HMG-CoA reductase inhibitor.   The HMG-CoA reductase inhibitor is fluvastatin, lovastatin, pravastatin, atorvastatin, simvastatin, cerivastatin, rivastatin, mevastatin, verostatin, compactin, dalvastatin, fluindostatin, rosuvastatin, pitivastatin, dihydrocompactin, and their pharmaceutical 2. The unit dosage form of claim 1, wherein the unit dosage form is selected from the group consisting of:   The cholesteryl ester transfer protein inhibitor is represented by Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, Formula IX, Formula X, Formula XI, Formula XII, Formula XIII, Formula XIV. 2. The unit dosage form of claim 1, selected from the group consisting of a compound of formula XV, formula XVI, formula XVII, formula XVIII and formula XIX.   The acidic concentrated polymer is hydroxypropylmethylcellulose succinate, hydroxypropylmethylcellulose succinate, hydroxypropylcellulose succinate, hydroxyethylmethylcellulose succinate, hydroxyethylcellulose succinate, hydroxypropylmethylcellulose phthalate, hydroxyethyl acetate succinate Methylcellulose, hydroxyethylmethylcellulose acetate phthalate, carboxyethylcellulose, carboxymethylcellulose, ethylcarboxymethylcellulose, carboxymethylethylcellulose, cellulose acetate phthalate, methylcellulose phthalate acetate, ethylcellulose phthalate acetate, hydroxypropylcellulose phthalate acetate, hydroxypropyl phthalate acetate Methylse Loose, hydroxypropyl cellulose succinate phthalate, hydroxypropyl methyl cellulose succinate phthalate, hydroxypropyl methyl cellulose phthalate succinate, cellulose phthalate propionate, hydroxypropyl cellulose butyrate phthalate, cellulose acetate trimellitic acid, methyl cellulose acetate trimellitic acid , Ethyl cellulose trimellitic acid acetate, hydroxypropyl cellulose trimellitic acid acetate, hydroxypropyl methylcellulose trimellitic acid acetate, hydroxypropyl cellulose trimellitic acid acetate, cellulose trimellitic acid propionate, cellulose trimellitic acid butyrate, cellulose terephthalate, cellulose acetate isophthalate, Cellulose acetate pyridinedicarboxylate, cellulose salicylate , Selected from the group consisting of hydroxypropyl cellulose salicylate, cellulose acetate ethyl benzoate, cellulose acetate hydroxypropyl ethyl benzoate, cellulose acetate ethyl phthalate, cellulose acetate ethyl nicotinate, cellulose acetate ethyl picolinate, and mixtures thereof The unit dosage form of claim 1.   2. The unit dosage form according to claim 1, wherein at least one of the cholesteryl ester transfer protein inhibitor composition and the HMG-CoA reductase inhibitor composition further comprises a base.   10. The unit dosage form of any one of claims 1-9, wherein the cholesteryl ester transfer protein inhibitor is torcetrapib and the HMG-CoA reductase inhibitor is atorvastatin or a pharmaceutically acceptable form thereof. . A method of forming a unit dosage form:
(a) forming an amorphous solid dispersion containing a cholesteryl ester transfer protein inhibitor and a concentrated polymer; and
(b) combining the amorphous solid dispersion with an HMG-CoA reductase inhibitor to form the unit dosage form;
Wherein the amorphous solid dispersion and the HMG-CoA reductase inhibitor are such that the amorphous solid dispersion and the HMG-CoA reductase inhibitor are substantially separated from each other within the dosage form. Combined, said method.   The step (b) further comprises forming a number of granules containing the amorphous solid dispersion, further forming an HMG-CoA reductase inhibitor composition, and then the HMG-CoA reductase inhibitor 14. The method of claim 13, comprising mixing a composition with the multiple granules.   The step (b) further includes the step of forming at least two layers, at least one of the layers contains the amorphous solid dispersion, and the other of the layers is the HMG-CoA reductase inhibitor 14. The method of claim 13, comprising:

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